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Supplementary Online Content

Hauberg ME, Roussos P, Grove J, Børglum AD, Mattheisen M; Schizophrenia Working Group of the Psychiatric Genomics Consortium. Analyzing the role of microRNAs in schizophrenia in the context of common genetic risk variants. JAMA Psychiatry. Published online March 9, 2016. doi:10.1001/jamapsychiatry.2015.3018.

eAppendix 1. Members of the Schizophrenia Working Group of the Psychiatric Genomics Consortium eAppendix 2. Supplemental Text eReferences eFigure 1. Circos plot for the MHC-region. eFigure 2. Clustering of the top-10 scoring miRNA families. eFigure 3. Region plots of GWAS associations for the miR-9-5p host genes. eFigure 4. Spatiotemporal brain expression of MIR137, MIR2682, and MIR9-2. eFigure 5. PPI-network of the miR-9-5p targetome. eFigure 6. Venn diagrams of the miR-9-5p/miR-137 and miR-137/-miR-2682-5p targetomes. eTable 1. Full results of the TargetScan conserved miRNA gene set analysis. eTable 2. Alternative TargetScan gene set analysis: longer clumping range. eTable 3. Alternative TargetScan gene set analysis: lower LD-threshold. eTable 4. Alternative TargetScan gene set analysis: lower LD-threshold and longer clumping range. eTable 5. Validation of top-10 gene sets using MiRanda target predictions. eTable 6. Validation of top-10 gene sets using TargetMiner target predictions. eTable 7. Results for the top-10 gene sets filtered with CLIP-data from 58 experiments. eTable 8. Signal for the top-10 gene sets in three unrelated traits. eTable 9. Functional annotation of genes regulated by the top-10 miRNA – biological processes. eTable 10. Functional annotation of genes regulated by the top-10 miRNA – annotation clusters. eTable 11. The top 50 most schizophrenia-associated genes targeted by miR-9-5p. eTable 12. Functional annotation of genes regulated by miR-9-5p – biological processes. eTable 13. Functional annotation of genes regulated by miR-9-5p – annotation clusters. eTable 14. Functional annotation of genes regulated by miR-9-5p – transcription factors. eTable 15. Genes in the schizophrenia enriched miR-9-5p subset. eTable 16. Gene set results for miRNA in schizophrenia GWAS loci. eTable 17. Gene set results for miRNA in schizophrenia CNVs.

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eAppendix 1. Members of the Schizophrenia Working Group of the Psychiatric Genomics Consortium Stephan Ripke1,2, Benjamin M. Neale1,2,3,4, Aiden Corvin5, James T. R. Walters6, Kai-How Farh1, Peter A. Holmans6,7, Phil Lee1,2,4, Brendan Bulik-Sullivan1,2, David A. Collier8,9, Hailiang Huang1,3, Tune H. Pers3,10,11, Ingrid Agartz12,13,14, Esben Agerbo15,16,17, Margot Albus18, Madeline Alexander19, Farooq Amin20,21, Silviu A. Bacanu22, Martin Begemann23, Richard A Belliveau Jr2, Judit Bene24,25, Sarah E. Bergen 2,26, Elizabeth Bevilacqua2, Tim B Bigdeli 22, Donald W. Black27, Richard Bruggeman28, Nancy G. Buccola29, Randy L. Buckner30,31,32, William Byerley33, Wiepke Cahn34, Guiqing Cai35,36, Murray J. Cairns39,120,170, Dominique Campion37, Rita M. Cantor38, Vaughan J. Carr39,40, Noa Carrera6, Stanley V. Catts39,41, Kimberly D. Chambert2, Raymond C. K. Chan42, Ronald Y. L. Chen43, Eric Y. H. Chen43,44, Wei Cheng45, Eric F. C. Cheung46, Siow Ann Chong47, C. Robert Cloninger48, David Cohen49, Nadine Cohen50, Paul Cormican5, Nick Craddock6,7, James J. Crowley51, David Curtis52,53, Michael Davidson54, Kenneth L. Davis36, Franziska Degenhardt55,56, Jurgen Del Favero57, Lynn E. DeLisi128,129 , Ditte Demontis17,58,59, Dimitris Dikeos60, Timothy Dinan61, Srdjan Djurovic14,62, Gary Donohoe5,63, Elodie Drapeau36, Jubao Duan64,65, Frank Dudbridge66, Naser Durmishi67, Peter Eichhammer68, Johan Eriksson69,70,71, Valentina Escott-Price6, Laurent Essioux72, Ayman H. Fanous73,74,75,76, Martilias S. Farrell51, Josef Frank77, Lude Franke78, Robert Freedman79, Nelson B. Freimer80, Marion Friedl81, Joseph I. Friedman36, Menachem Fromer1,2,4,82, Giulio Genovese2, Lyudmila Georgieva6, Elliot S. Gershon209, Ina Giegling81,83, Paola Giusti-Rodríguez51, Stephanie Godard84, Jacqueline I. Goldstein1,3, Vera Golimbet85, Srihari Gopal86, Jacob Gratten87, Lieuwe de Haan88, Christian Hammer23, Marian L. Hamshere6, Mark Hansen89, Thomas Hansen17,90, Vahram Haroutunian36,91,92, Annette M. Hartmann81, Frans A. Henskens39,93,94, Stefan Herms55,56,95, Joel N. Hirschhorn3,11,96, Per Hoffmann55,56,95, Andrea Hofman55,56, Mads V. Hollegaard97, David M. Hougaard97, Masashi Ikeda98, Inge Joa99, Antonio Julià100, René S. Kahn34, Luba Kalaydjieva101,102, Sena Karachanak-Yankova103, Juha Karjalainen78, David Kavanagh6, Matthew C. Keller104, Brian J. Kelly120, James L. Kennedy105,106,107, Andrey Khrunin108, Yunjung Kim51, Janis Klovins109, James A. Knowles110, Bettina Konte81, Vaidutis Kucinskas111, Zita Ausrele Kucinskiene111, Hana Kuzelova-Ptackova112, Anna K. Kähler26, Claudine Laurent19,113, Jimmy Lee Chee Keong47,114, S. Hong Lee87, Sophie E. Legge6, Bernard Lerer115, Miaoxin Li43,44,116 Tao Li117, Kung-Yee Liang118, Jeffrey Lieberman119, Svetlana Limborska108, Carmel M. Loughland39,120, Jan Lubinski121, Jouko Lönnqvist122, Milan Macek Jr112, Patrik K. E. Magnusson26, Brion S. Maher123, Wolfgang Maier124, Jacques Mallet125, Sara Marsal100, Manuel Mattheisen17,58,59,126, Morten Mattingsdal14,127, Robert W. McCarley128,129, Colm McDonald130, Andrew M. McIntosh131,132, Sandra Meier77, Carin J. Meijer88, Bela Melegh24,25, Ingrid Melle14,133, Raquelle I. Mesholam-Gately128,134, Andres Metspalu135, Patricia T. Michie39,136, Lili Milani135, Vihra Milanova137, Younes Mokrab8, Derek W. Morris5,63, Ole Mors17,58,138, Kieran C. Murphy139, Robin M. Murray140, Inez Myin-Germeys141, Bertram Müller-Myhsok142,143,144, Mari Nelis135, Igor Nenadic145, Deborah A. Nertney146, Gerald Nestadt147, Kristin K. Nicodemus148, Liene Nikitina-Zake109, Laura Nisenbaum149, Annelie Nordin150, Eadbhard O’Callaghan151, Colm O’Dushlaine2, F. Anthony O’Neill152, Sang-Yun Oh153, Ann Olincy79, Line Olsen17,90, Jim Van Os141,154, Psychosis Endophenotypes International Consortium155, Christos Pantelis39,156, George N. Papadimitriou60, Sergi Papiol23, Elena Parkhomenko36, Michele T. Pato110, Tiina Paunio157,158, Milica Pejovic-Milovancevic159, Diana O. Perkins160, Olli Pietiläinen158,161, Jonathan Pimm53, Andrew J. Pocklington6, John Powell140, Alkes Price3,162, Ann E. Pulver147, Shaun M. Purcell82, Digby Quested163, Henrik B. Rasmussen17,90, Abraham Reichenberg36, Mark A. Reimers164, Alexander L. Richards6, Joshua L. Roffman30,32, Panos Roussos82,165, Douglas M. Ruderfer6,82, Veikko Salomaa71, Alan R. Sanders64,65, Ulrich Schall39,120, Christian R. Schubert166, Thomas G. Schulze77,167, Sibylle G. Schwab168, Edward M. Scolnick2, Rodney J. Scott39,169,170, Larry J. Seidman128,134, Jianxin Shi171, Engilbert Sigurdsson172, Teimuraz Silagadze173, Jeremy M. Silverman36,174, Kang Sim47, Petr Slominsky108, Jordan W. Smoller2,4, Hon-Cheong So43, Chris C. A. Spencer175, Eli A. Stahl3,82, Hreinn Stefansson176, Stacy Steinberg176, Elisabeth Stogmann177, Richard E. Straub178, Eric Strengman179,34, Jana Strohmaier77, T. Scott Stroup119, Mythily Subramaniam47, Jaana Suvisaari122, Dragan M. Svrakic48, Jin P. Szatkiewicz51, Erik Söderman12, Srinivas Thirumalai180, Draga Toncheva103, Paul A. Tooney39,120,170 , Sarah Tosato181, Juha Veijola182,183, John Waddington184, Dermot Walsh185, Dai Wang86, Qiang Wang117, Bradley T. Webb22, Mark Weiser54, Dieter B. Wildenauer186, Nigel M. Williams6, Stephanie Williams51, Stephanie H. Witt77, Aaron R. Wolen164, Emily H. M. Wong43, Brandon K. Wormley22, Jing Qin Wu39,170, Hualin Simon Xi187, Clement C. Zai105,106, Xuebin Zheng188, Fritz Zimprich177, Naomi R. Wray87, Kari Stefansson176, Peter M. Visscher87, Wellcome Trust Case-Control Consortium 2189, Rolf Adolfsson150, Ole A. Andreassen14,133, Douglas H. R. Blackwood132, Elvira Bramon190, Joseph D. Buxbaum35,36,91,191, Anders D. Børglum17,58,59,138, Sven Cichon55,56,95,192, Ariel Darvasi193, Enrico Domenici194, Hannelore Ehrenreich23, Tõnu Esko3,11,96,135, Pablo V. Gejman64,65, Michael Gill5, Hugh Gurling53, Christina M. Hultman26, Nakao Iwata98, Assen V. Jablensky39,102,186,195, Erik G. Jönsson12,14, Kenneth S. Kendler196, George Kirov6, Jo Knight105,106,107, Todd Lencz197,198,199, Douglas F. Levinson19, Qingqin S. Li86, Jianjun Liu188,200, Anil K. Malhotra197,198,199, Steven A. McCarroll2,96, Andrew McQuillin53, Jennifer L. Moran2, Preben B. Mortensen15,16,17, Bryan J. Mowry87,201, Markus M. Nöthen55,56, Roel A. Ophoff38,80,34, Michael J. Owen6,7, Aarno Palotie2,4,161, Carlos N. Pato110, Tracey L. Petryshen2,128,202, Danielle Posthuma203,204,205, Marcella Rietschel77, Brien P. Riley196, Dan Rujescu81,83, Pak C. Sham43,44,116 Pamela Sklar82,91,165, David St Clair206, Daniel R. Weinberger178,207, Jens R. Wendland166, Thomas Werge17,90,208, Mark J. Daly1,2,3, Patrick F. Sullivan26,51,160 & Michael C. O’Donovan6,7

Affiliations: 1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. 2Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. 3Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. 4Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. 5Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin 8, Ireland. 6MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, CF24 4HQ, UK. 7National Centre for Mental Health, Cardiff University, Cardiff,


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CF24 4HQ, UK. 8Eli Lilly and Company Limited, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey, GU20 6PH, UK. 9Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London, SE5 8AF, UK. 10Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, DK-2800, Denmark. 11Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, Massachusetts, 02115USA. 12Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, SE-17176 Stockholm, Sweden. 13Department of Psychiatry, Diakonhjemmet Hospital, 0319 Oslo, Norway. 14NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, 0424 Oslo, Norway. 15Centre for Integrative Register-based Research, CIRRAU, Aarhus University, DK-8210 Aarhus, Denmark. 16National Centre for Register-based Research, Aarhus University, DK-8210 Aarhus, Denmark. 17The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Denmark. 18State Mental Hospital, 85540 Haar, Germany. 19Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, USA. 20Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, Atlanta, Georgia 30033, USA. 21Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta Georgia 30322, USA. 22Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia 23298, USA. 23Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen 37075, Germany. 24Department of Medical Genetics, University of Pécs, Pécs H-7624, Hungary. 25Szentagothai Research Center, University of Pécs, Pécs H-7624, Hungary. 26Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-17177, Sweden. 27Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA. 28University Medical Center Groningen, Department of Psychiatry, University of Groningen NL-9700 RB, The Netherlands. 29School of Nursing, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112, USA. 30Athinoula A. Martinos Center, Massachusetts General Hospital, Boston, Massachusetts 02129, USA. 31Center for Brain Science, Harvard University, Cambridge, Massachusetts, 02138 USA. 32Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, 02114 USA. 33Department of Psychiatry, University of California at San Francisco, San Francisco, California, 94143 USA. 34University Medical Center Utrecht, Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, 3584 Utrecht, The Netherlands. 35Department of Human Genetics, Icahn School of Medicine at Mount Sinai, New York, New York 10029 USA. 36Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029 USA. 37Centre Hospitalier du Rouvray and INSERM U1079 Faculty of Medicine, 76301 Rouen, France. 38Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA. 39Schizophrenia Research Institute, Sydney NSW 2010, Australia. 40School of Psychiatry, University of New South Wales, Sydney NSW 2031, Australia. 41Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, St Lucia QLD 4072, Australia. 42Institute of Psychology, Chinese Academy of Science, Beijing 100101, China. 43Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. 44State Key Laboratory for Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. 45Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina 27514, USA. 46Castle Peak Hospital, Hong Kong, China. 47Institute of Mental Health, Singapore 539747, Singapore. 48Department of Psychiatry, Washington University, St. Louis, Missouri 63110, USA. 49Department of Child and Adolescent Psychiatry, Assistance Publique Hopitaux de Paris, Pierre and Marie Curie Faculty of Medicine and Institute for Intelligent Systems and Robotics, Paris, 75013, France. 50 Blue Note Biosciences, Princeton, New Jersey 08540, USA 51Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599-7264, USA. 52Department of Psychological Medicine, Queen Mary University of London, London E1 1BB, UK. 53Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London WC1E 6JJ, UK. 54Sheba Medical Center, Tel Hashomer 52621, Israel. 55Department of Genomics, Life and Brain Center, D-53127 Bonn, Germany. 56Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany. 57Applied Molecular Genomics Unit, VIB Department of Molecular Genetics, University of Antwerp, B-2610 Antwerp, Belgium. 58Centre for Integrative Sequencing, iSEQ, Aarhus University, DK-8000 Aarhus C, Denmark. 59Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark. 60First Department of Psychiatry, University of Athens Medical School, Athens 11528, Greece. 61Department of Psychiatry, University College Cork, Co. Cork, Ireland. 62Department of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway. 63Cognitive Genetics and Therapy Group, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Co. Galway, Ireland. 64Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois 60637, USA. 65Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, Illinois 60201, USA. 66Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK. 67Department of Child and Adolescent Psychiatry, University Clinic of Psychiatry, Skopje 1000, Republic of Macedonia. 68Department of Psychiatry, University of Regensburg, 93053 Regensburg, Germany. 69Department of General Practice, Helsinki University Central Hospital, University of Helsinki P.O. Box 20, Tukholmankatu 8 B, FI-00014, Helsinki, Finland 70Folkhälsan Research Center, Helsinki, Finland, Biomedicum Helsinki 1, Haartmaninkatu 8, FI-00290, Helsinki, Finland.71National Institute for Health and Welfare, P.O. BOX 30, FI-00271 Helsinki, Finland.72Translational Technologies and Bioinformatics, Pharma Research and Early Development, F. Hoffman-La Roche, CH-4070 Basel, Switzerland. 73Department of Psychiatry, Georgetown University School of Medicine, Washington DC 20057, USA. 74Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA. 75Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA. 76Mental Health Service Line, Washington VA Medical Center, Washington DC 20422, USA. 77Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg , D-68159 Mannheim, Germany. 78Department of Genetics, University of Groningen, University Medical Centre Groningen, 9700 RB Groningen, The Netherlands. 79Department of Psychiatry, University of Colorado Denver, Aurora, Colorado 80045, USA. 80Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California 90095, USA. 81Department of Psychiatry, University of Halle, 06112 Halle, Germany. 82Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. 83Department of Psychiatry, University of Munich, 80336, Munich, Germany.


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84Departments of Psychiatry and Human and Molecular Genetics, INSERM, Institut de Myologie, Hôpital de la Pitiè-Salpêtrière, Paris, 75013, France. 85Mental Health Research Centre, Russian Academy of Medical Sciences, 115522 Moscow, Russia. 86Neuroscience Therapeutic Area, Janssen Research and Development, Raritan, New Jersey 08869, USA. 87Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, QLD 4072, Australia. 88Academic Medical Centre University of Amsterdam, Department of Psychiatry, 1105 AZ Amsterdam, The Netherlands. 89Illumina, La Jolla, California, California 92122, USA. 90Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, DK-4000, Denmark. 91Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. 92J. J. Peters VA Medical Center, Bronx, New York, New York 10468, USA. 93Priority Research Centre for Health Behaviour, University of Newcastle, Newcastle NSW 2308, Australia. 94School of Electrical Engineering and Computer Science, University of Newcastle, Newcastle NSW 2308, Australia. 95Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, CH-4058, Switzerland. 96Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. 97Section of Neonatal Screening and Hormones, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, DK-2300, Denmark. 98Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, 470-1192, Japan. 99Regional Centre for Clinical Research in Psychosis, Department of Psychiatry, Stavanger University Hospital, 4011 Stavanger, Norway. 100Rheumatology Research Group, Vall d'Hebron Research Institute, Barcelona, 08035, Spain. 101Centre for Medical Research, The University of Western Australia, Perth, WA 6009, Australia. 102The Perkins Institute for Medical Research, The University of Western Australia, Perth, WA 6009, Australia.103Department of Medical Genetics, Medical University, Sofia1431, Bulgaria. 104Department of Psychology, University of Colorado Boulder, Boulder, Colorado 80309, USA. 105Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, M5T 1R8, Canada. 106Department of Psychiatry, University of Toronto, Toronto, Ontario, M5T 1R8, Canada. 107Institute of Medical Science, University of Toronto, Toronto, Ontario, M5S 1A8, Canada. 108Institute of Molecular Genetics, Russian Academy of Sciences, Moscow123182, Russia. 109Latvian Biomedical Research and Study Centre, Riga, LV-1067, Latvia. 110Department of Psychiatry and Zilkha Neurogenetics Institute, Keck School of Medicine at University of Southern California, Los Angeles, California 90089, USA. 111Faculty of Medicine, Vilnius University, LT-01513 Vilnius, Lithuania. 112 Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic. 113 Department of Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine, Paris 75013, France. 114Duke-NUS Graduate Medical School, Singapore 169857, Singapore. 115Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. 116Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, China.117Mental Health Centre and Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. 118Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. 119Department of Psychiatry, Columbia University, New York, New York 10032, USA. 120Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle NSW 2300, Australia.121Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, 70-453 Szczecin, Poland. 122Department of Mental Health and Substance Abuse Services; National Institute for Health and Welfare, P.O. BOX 30, FI-00271 Helsinki, Finland 123Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA. 124Department of Psychiatry, University of Bonn, D-53127 Bonn, Germany. 125Centre National de la Recherche Scientifique, Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, Hôpital de la Pitié Salpêtrière, 75013, Paris, France. 126Department of Genomics Mathematics, University of Bonn, D-53127 Bonn, Germany. 127Research Unit, Sørlandet Hospital, 4604 Kristiansand, Norway. 128Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, USA. 129VA Boston Health Care System, Brockton, Massachusetts 02301, USA. 130Department of Psychiatry, National University of Ireland Galway, Co. Galway, Ireland. 131Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh EH16 4SB, UK. 132Division of Psychiatry, University of Edinburgh, Edinburgh EH16 4SB, UK. 133Division of Mental Health and Addiction, Oslo University Hospital, 0424 Oslo, Norway. 134Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, Massachusetts 02114, USA. 135Estonian Genome Center, University of Tartu, Tartu 50090, Estonia. 136School of Psychology, University of Newcastle, Newcastle NSW 2308, Australia. 137First Psychiatric Clinic, Medical University, Sofia 1431, Bulgaria. 138Department P, Aarhus University Hospital, DK-8240 Risskov, Denmark. 139Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin 2, Ireland. 140King’s College London, London SE5 8AF, UK. 141Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, EURON, 6229 HX Maastricht, The Netherlands. 142Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK. 143Max Planck Institute of Psychiatry, 80336 Munich, Germany. 144Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany. 145Department of Psychiatry and Psychotherapy, Jena University Hospital, 07743 Jena, Germany. 146Department of Psychiatry, Queensland Brain Institute and Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, St Lucia QLD 4072, Australia. 147Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. 148Department of Psychiatry, Trinity College Dublin, Dublin 2, Ireland. 149Eli Lilly and Company, Lilly Corporate Center, Indianapolis, 46285 Indiana, USA. 150Department of Clinical Sciences, Psychiatry, Umeå University, SE-901 87 Umeå, Sweden. 151DETECT Early Intervention Service for Psychosis, Blackrock, Co. Dublin, Ireland. 152Centre for Public Health, Institute of Clinical Sciences, Queen’s University Belfast, Belfast BT12 6AB, UK. 153Lawrence Berkeley National Laboratory, University of California at Berkeley, Berkeley, California 94720, USA. 154Institute of Psychiatry, King’s College London, London SE5 8AF, UK. 155A list of authors and affiliations appear in the Supplementary Information of the original article. 156Melbourne Neuropsychiatry Centre, University of Melbourne & Melbourne Health, Melbourne, Vic 3053, Australia. 157Department of Psychiatry, University of Helsinki, P.O. Box 590, FI-00029 HUS, Helsinki, Finland. 158Public Health Genomics Unit, National Institute for Health and Welfare, P.O. BOX 30, FI-00271 Helsinki, Finland 159Medical Faculty, University of Belgrade, 11000 Belgrade, Serbia. 160Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina 27599-7160, USA. 161Institute for Molecular Medicine Finland, FIMM, University of Helsinki, P.O. Box 20FI-00014, Helsinki, Finland 162Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts


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02115, USA. 163Department of Psychiatry, University of Oxford, Oxford, OX3 7JX, UK. 164Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia 23298, USA. 165Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. 166PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, USA. 167Department of Psychiatry and Psychotherapy, University of Gottingen, 37073 Göttingen, Germany. 168Psychiatry and Psychotherapy Clinic, University of Erlangen, 91054 Erlangen, Germany. 169Hunter New England Health Service, Newcastle NSW 2308, Australia. 170School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan NSW 2308, Australia. 171Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA. 172University of Iceland, Landspitali, National University Hospital, 101 Reykjavik, Iceland. 173Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), N33, 0177 Tbilisi, Georgia. 174Research and Development, Bronx Veterans Affairs Medical Center, New York, New York 10468, USA. 175Wellcome Trust Centre for Human Genetics, Oxford, OX3 7BN, UK. 176deCODE Genetics, 101 Reykjavik, Iceland. 177Department of Clinical Neurology, Medical University of Vienna, 1090 Wien, Austria. 178Lieber Institute for Brain Development, Baltimore, Maryland 21205, USA. 179Department of Medical Genetics, University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands. 180Berkshire Healthcare NHS Foundation Trust, Bracknell RG12 1BQ, UK. 181Section of Psychiatry, University of Verona, 37134 Verona, Italy. 182Department of Psychiatry, University of Oulu, P.O. BOX 5000, 90014, Finland183University Hospital of Oulu, P.O.BOX 20, 90029 OYS, Finland.184Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin 2, Ireland. 185Health Research Board, Dublin 2, Ireland. 186School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth WA6009, Australia. 187Computational Sciences CoE, Pfizer Worldwide Research and Development, Cambridge, Massachusetts 02139, USA.188Human Genetics, Genome Institute of Singapore, A*STAR, Singapore 138672, Singapore. 189A list of authors and affiliations appear in the Supplementary Information in the original article.190University College London, London WC1E 6BT, UK. 191Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. 192Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, 52428 Juelich, Germany. 193Department of Genetics, The Hebrew University of Jerusalem, 91905 Jerusalem, Israel. 194Neuroscience Discovery and Translational Area, Pharma Research and Early Development, F. Hoffman-La Roche, CH-4070 Basel, Switzerland. 195Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Medical Research Foundation Building, Perth WA 6000, Australia. 196Virginia Institute for Psychiatric and Behavioral Genetics, Departments of Psychiatry and Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298, USA. 197The Feinstein Institute for Medical Research, Manhasset, New York, 11030 USA. 198The Hofstra NS-LIJ School of Medicine, Hempstead, New York, 11549 USA. 199The Zucker Hillside Hospital, Glen Oaks, New York,11004 USA. 200Saw Swee Hock School of Public Health, National University of Singapore, Singapore 117597, Singapore. 201Queensland Centre for Mental Health Research, University of Queensland, Brisbane 4076, Queensland, Australia. 202Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. 203Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam 3000, The Netherlands. 204Department of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, Amsterdam 1081, The Netherlands. 205Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam 1081, The Netherlands. 206University of Aberdeen, Institute of Medical Sciences, Aberdeen, AB25 2ZD, UK. 207Departments of Psychiatry, Neurology, Neuroscience and Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA. 208Department of Clinical Medicine, University of Copenhagen, Copenhagen 2200, Denmark.209Departments of Psychiatry and Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.


6


eAppendix 2. Supplemental Text OverviewofmethodsforestablishingthetargetomeofamiRNA 7

FilteringofpredictedmiRNAtargetswithCLIPdata 8

ThecorrelationbetweenthenumberofmiRNAbindingsitesinageneandschizophrenia 9

CircosplotfortheMHCregion(targetsoftop‐10miRNA) 10

Clusteringoftop10miRNAgenesetsconsideringonlyschizophreniaassociatedgenes 11

Regionalassociationplotsofthethreemir‐9hostgenes 12

TemporalbrainexpressionofmiR‐9‐5p,miR‐137,andmiR‐2682‐5p 13

ClusteringofmiR‐9‐5ptargets 14

PPInetworkformiR‐9‐5ptargets 15

AnalysisofthemiR‐9‐5ptargetomeinpostmortembrains 16

DeterminingifthetargetomeoverlapbetweentwomiRNAisbiggerthanexpectedbychance 18

AnoteonthelimitedsupportforanassociationofthemiR‐130bandmiR‐193a‐3ptargetomes 19

eReferences 20


7


Overview of methods for establishing the targetome of a miRNA It is widely accepted that miRNA bind to the 3’-UTR, but there is also evidence for binding in coding regions1,2. This pairing involves in most cases a so-called seed sequence with certain patterns of complementarity. However, it has also been shown that miRNA interact without such seed sequences albeit with lower average effects3. In order to establish a list of all genes, that are targeted by a given miRNA (the so-called targetome of a miRNA), computational prediction have been used extensively. In these computational prediction methods, an array of different characteristics are taken into account such as conservation across species, local AU content, predicted accessibility due to RNA folding, Gibbs energy of the interaction, and expression data. However, the prediction algorithms still suffer from limited specificity and/or sensitivity despite over a decade of research. As an alternative to these computational prediction methods various experimental methods exist. These include reporter assays, which suffer from their low throughput, and overexpression/silencing experiments measuring the change in protein abundance resulting from altered miRNA expression. Another experimental approach is cross-linked immunoprecipitation (CLIP) experiments where the miRNA, its associated proteins, and the fragment of mRNA that it binds are precipitated and subsequently RNA sequencing is carried out. This gives the abundance of each miRNA expressed in the tissue/cell as well as the target sites on the genes. However, subsequently computer algorithms have to be employed to predict which miRNA binds to which target sites. A relatively new approach which circumvents this limitation is “CLASH” which is similar to CLIP experiments, but with the difference that the miRNA and the fragment of the mRNA to which it binds are ligated3. Unfortunately, this has only been used in yeast and in HEK cells and the authors demonstrated a depletion of brain-expressed miRNA in the experiments. In our paper, we opted to primarily use the predicted conserved predicted targets of the widely used TargetScan. Because of its reliance on conservation and that the miRNA have a seed site, the predicted targets of this algorithm have a relatively high chance of being both true predictions and functionally important. For validation purposes, two alternative prediction methods, were used: The recent methods TargetMiner4, which is based on mirBase 18, and the broadly used but slightly older MiRanda5, which is based on mirBase 15, were used.


8


Filtering of predicted miRNA targets with CLIP data We used data from AGO cross-linked immunoprecipitation (CLIP) experiments in an attempt to remove false predictions from our TargetScan gene sets. Results from 41 CLIP experiments in human and mouse were down-loaded from StarBase6. Additionally, one experiment from human brain7 and a group of experiments including mainly hematopoietic cells8 were included. LiftOver was used to lift results from hg18 and from mm9 to hg19. Peaks longer than 300 bp were excluded from the analysis due to lack of specificity (this represented 0.6% of all peaks). A miRNA target site was defined to be supported by CLIP data if the seed-region of the target site was completely within the peak. In a subsequent analysis we determined whether filtering of our top ranking conserved miRNA gene sets with the aforementioned CLIP data led to an increased enrichment for schizophrenia associated genes. In other words, we tested whether filtering with CLIP data was better than removing genes at random. For each of our top miR-NA gene sets, 1000 replicate gene sets were generated by drawing genes from the original non-filtered gene set until the replicate set contained the same number of genes as the CLIP filtered gene set. Subsequently, the IN-RICH p-values of these replicate sets under the top-1% clumping threshold were compared to the p-values of the original CLIP filtered gene sets by counting how many replicate sets that had as strong or a stronger association to schizophrenia. This resulted in empirical p-values for the following four top ranked miRNA: miR-9-5p ~ p=0.16; miR-485-5p ~ p=0.064; miR-137 ~ p=0.16; and miR-101-3p ~ p=0.24. While filtering with CLIP data showed an overall trend to improve our enrichment p-values there was no significant evidence that filtering with CLIP data was better than removing genes at random. We note that our analysis was limited by the availability of relevant CLIP data and that only two brain related datasets could be incorporated. Thus, many of the CLIP supported targets in our top gene sets therefore come from samples other than the two CLIP experiments from brain. For miR-9-5p, the human brain experiment has 6 targets (0.49% of targets from that experiment) and the p13 mouse brain contains 143 (3.3% of targets from that experiment).


9


The correlation between the number of miRNA binding sites in a gene and schizophrenia To determine whether miRNA regulated genes were more likely to be schizophrenia risk genes, we tested if genes under extensive miRNA regulation showed a stronger association with schizophrenia compared to genes with reduced or missing miRNA regulation. More precisely, we tested if there was a correlation between the number of predicted miRNA target sites per gene and the corresponding strength of association with schizophre-nia. The p-value assigned to a gene (strength of association) was the p-value of the most significantly associated SNP physically located within the gene (min p). Genes in the broader MHC-region were excluded. A linear model for the gene p-value was run including the following independent variables: the number of miRNA target sites in the gene, the log-transformed gene length, and the 3’-UTR length. This model looked like this:

log10(p‐value) ~ miRNA target sites + 3’UTR length + gene length

Estimate Std. Error t value Pr(>|t|)

(Intercept) ‐1.939e+00 1.366e‐02 ‐141.905 <2e‐16

miRNA target sites ‐1.586e‐02 1.575e‐03 ‐10.072 <2e‐16

3’UTR length ‐3.471e‐05 7.678e‐06 ‐4.521 6.2e‐06

gene length ‐3.165e‐06 8.009e‐08 ‐39.522 <2e‐16 This shows that our covariates are also associated with the gene p-value. We further note that miRNA target sites are also significantly correlated with the 3’UTR length and the gene length and that the identified association was in the same order of magnitude when omitting the correction for 3’-UTR length (data not shown). We subsequently calculated the fraction of the variance in the GWAS results solely explained by the number of miRNA target sites, regressing out effects of gene 3’-UTR length. In addition to the calculations for schizophre-nia both of the two abovementioned approaches were also repeated for the three unrelated traits9-12 . The results for the correlation between miRNA gene target sites and gene p-value were (sample size is number of cases and controls in the respective study):

Trait beta p‐value variance explained Sample size

Schizophrenia9 ‐1.59E‐02 <2e‐16 0.49% 150,064

Age at Menarche10 ‐8.20E‐03 3.00E‐09 0.20% 182,416

Crohn's11 ‐3.69E‐03 0.06169 0.02% 66,968

Height12 ‐5.41E‐02 <2e‐16 0.52% 253,288

For schizophrenia the analysis shows a trait unspecific correlation of gene p-values with the number of miRNA target sites per gene. In other words, genes with more miRNA target sites on average had a lower p-value. Simi-lar associations were found for age at menarche and height but not for Crohn’s disease.


10


Circos plot for the MHC region (targets of top-10 miRNA) To provide an overview of the targets of the top-10 miRNA in the MHC-region, we provide eFigure 1. eFigure 1: Circos plot for the MHC-region.

A zoomed in version of the MHC-region of the Circos plot in the main article. Note that the genes in this region were excluded from the gene set analyses. GW: genome-wide.


11


Clustering of top 10 miRNA gene sets considering only schizophrenia associ-ated genes To see how the top-10 scoring miRNA gene sets related when considering only schizophrenia associated genes, they were clustered considering only genes at various cut-offs for the gene’s association with schizophrenia (eFigure 2). Genes in the broader MHC-region and on sex-chromosomes were excluded in the analysis. eFigure 2: Clustering of the top-10 scoring miRNA families.

The clustering was based on the Jaccard distance between their target genes on autosomes outside the MHC-region considering a) all genes, b) genes within top 5% of SNPs c) genes within top 1% of SNPs d) genes with p < 1 x 10-5, and e) genes with p < 5 x 10-8 (Genome-wide significant).

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d) e)


12


Regional association plots of the three mir-9 host genes Ricopili (http://www.broadinstitute.org/mpg/ricopili/) was used to visualize association results from PGC2 in genomic regions harboring variants related to mir-9 (eFigure 3). eFigure 3: Region plots of GWAS associations for the miR-9-5p host genes.

The “PGC2” associations at a) MIR9-1 b) MIR9-2 c) MIR9-3. LINC00461 is the putative host gene of MIR9-2. The lead SNP (rs181900) is 25kb upstream of the longest isoform of this host gene and 43kb upstream of MIR9-2 itself.


13


Temporal brain expression of miR-9-5p, miR-137, and miR-2682-5p To establish the temporal expression pattern of selected miRNA, BrainSpan RNA sequencing data was used13. BrainSpan data includes a variable number of samples at various regions at various time points. In our analyses, only regions present in 30 or more samples were used. When more than one sample at a given region and devel-opmental stage was present, the average expression was used. The results of this analysis is presented in eFigure 4. eFigure 4: Spatiotemporal brain expression of MIR137, MIR2682, and MIR9-2.

MIR9-2 is the mir-9 expressing gene showing the highest expression in BrainSpan, and the second peak at 26 weeks in STC seen in its figure is from a single sample at a single time point, and can thus be an outlier. A1C: primary auditory cortex (core), AMY: amygdaloid complex, DFC: dorsolateral pre-frontal cortex, HIP: hippocampus (hippocampal formation), IPC: posteroventral (inferior) parietal cor-tex, ITC: inferolateral temporal cortex (area TEv), MFC: anterior (rostral) cingulate (medial prefrontal) cortex, OFC: orbital frontal cortex, STC: posterior (caudal) superior temporal cortex (area 22c), URL: upper (rostral) rhombic lip, V1C: primary visual cortex (striate cortex), VFC: ventrolateral prefrontal cortex.

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14


Clustering of miR-9-5p targets In an attempt to identify homogeneous subsets (functional groups) in the genes targeted by miR-9-5p, we em-ployed a hierarchically clustering approach using data from BrainSpan13. Brain RNA sequencing reads per kilobase per million mapped tags (RPKM) were averaged across different developmental time points and brain regions (see below) and log transformed with log2(1+RPKM) following guiding principles from BrainSpan. All miRNA targets in a gene set were hierarchically clustered using a Pearson correlation as similarity measure. We used data from all available brain regions at developmental stages prior to and including two years of age. The age cut-off was selected in accordance with the expression pattern of miR-9-5p (eFigure 4). Genes with no ex-pression data were excluded from the analyses. A cut-off height of 0.25 resulted in four groups of targets which had a gene set size larger than or equal to 50. To test a potential association of the resulting gene sets with schiz-ophrenia we used INRICH at the top-1% threshold:

Size Raw p‐value Gene set name

62 0.7726 Cluster 1111 0.1335 Cluster 2201 0.1158 Cluster 3497 1.34 x 10

‐4Cluster 4

1237 4.87 x 10‐5

Original set

One of the gene sets, cluster 4 (eTable 15), was significantly associated with schizophrenia. While the enrich-ment for cluster 4 was less significant when compared to the enrichment for the full set, the difference was only marginal. Since this cluster included less then half of the original targets we tested in a resampling procedure whether this group of genes was enriched for genes associated with schizophrenia. The INRICH p-value of this cluster was compared to that of 1000 size-matched gene sets drawn at random from all miR-9-5p targets in the original test. Only four of these randomly drawn subsets showed as strong or a stronger p-value for association in INRICH compared to the true subset. This resulted in an empirical p-value for the change in enrichment of p = (4+1)/(1000+1) = 5.0 x 10-3. Hence, taken the overall number of genes in this subgroup into account the cluster of 497 genes in the subgroup are relatively more enriched for schizophrenia associated genes than the original set even though the subset itself had a slightly less significant p-value than the original set..


15


PPI network for miR-9-5p targets eFigure 5: PPI-network of the miR-9-5p targetome. Hierarchical clustering using data from BrainSpan (see above) is one way to identify homogeneous subsets (functional groups) in genes targeted by miR-9-5p. Another way is to use data for protein-protein interactions (PPIs). We therefore used data from the TissueNet Brain PPIs14 to see if the subset of 497 genes (cluster 4), that was identified using BrainSpan data, had more PPIs than a random subset. For this we compared the number of PPIs in the original set to size-matched gene sets drawn randomly from all miR-9-5p targets. Of 100,000 gene sets two had as many or more PPIs as that of the original gene set yielding an empirical p-value of 3.0 x 10-5. We would like to note that co-expressed genes are in general expected to be enriched for PPIs and our finding does not itself provide further evidence for the involvement of the subset in schizophrenia. Instead, it adds credibility to our clustering approach as with a different data-set we are able to show that the genes have likely more shared functionality than a random subset. The PPI-network derived from the aforementioned TissueNet data for the original set of miR-9-5p targets and the subset of genes in cluster 4 is illustrated in eFigure 5.

Members of the identified subset and interactions between its members are colored in red. Genes with no PPIs are not shown.


16


Analysis of the miR-9-5p targetome in post mortem brains The information from BrainSpan and TissueNet (see above) are disease unspecific and based on information from healthy individuals. In order to further characterize the miR-9-5p targetome in relation to schizophrenia, we therefore looked at the enrichment of the miR-9-5p targetome in co-expression modules from post mortem brains of patients with schizophrenia and controls. Details on how these co-expression modules have been de-rived, the characterization of the modules and a full list of their genes can be found elsewhere15. The subsequent table shows p-values for the enrichment of genes in the aforementioned co-expression modules in both the full set of targets and the subset of 497 targets. Only nominally significant modules are listed. None of the modules survives correction for multiple testing (data not shown). Additionally, it is indicated whether these modules were differentially expressed in patients compared to controls. DEiS – Module differentially expressed in schiz-ophrenia (yes/no); # Genes – Number of targets in module.

Module p‐value for enrichment in module DEiS # Genes

All miR‐9‐5p targets (1237 genes)

MG3 2.2E‐04 yes 16

PV(+)1 7.6E‐04 no 125

OLIG3 4.1E‐03 no 13

UNK5 1.7E‐02 no 9

OLIG1 3.7E‐02 Yes 107

miR‐9‐5p subset (497 genes)

UNK1 3.0E‐04 no 44

UNK5 2.8E‐02 no 5

OLIG3 3.5E‐02 no 6

MG3 4.1E‐02 yes 6

Genes in modules Genes located in GWAS regions = clumps with p‐values < 1 x 10‐5 in PGC2 are underlined and printed in bold if the p‐value was < 5 x 10‐8 in PGC2. All miR‐9‐5p targets: MG3: ADAMTS9, ANXA2, CCDC50, CHSY1, CMTM6, COL4A2, EHD4, IL6R, ITGA6, KCTD12, MYH9, NRP1, TFRC, TGFBR1, TGFBR2, TMEM109

PV(+)1: AAK1, ABCA1, AKAP11, ALPL, ANK2, ANKH, ATP11C, ATP7A, ATXN3, B4GALNT1, BAIAP2, BNC2, BRPF3, BTBD10, C16orf70, C18orf25, C1QL1, C9orf89, CAPZA1, CBX7, CDC14B, CELSR2, CNTN4, COL18A1, COLEC12, CPEB3, DCP2, DCTN1, DR1, EFEMP1, EIF4E, ELAVL1, ELOVL4, ENTPD1, FAM81A, FBXO28, FKBP7, FLRT3, FNDC3B, FOXP2, FRMPD4, FRY, FYCO1, GABBR2, GLS, GLUD1, GOPC, GPR124, IGF2BP2, IPO4, ITM2C, JMY, JUP, KCTD2, KIAA1045, KIAA2013, KIF21A, LARP1, LASP1, LSM14A, MAP3K1, MEF2C, MICAL2, MKRN2, MYCBP, NAGPA, NAPB, NEDD1, NEDD4, NFATC3, NLGN4X, NMT1, NTNG1, OPCML, OPTN, OTUD3, PCSK2, PEG3, PHF15, PHF19, PJA2, PLEKHA1, PLEKHA2, PRKCA, PRKD3, PRRT3, PRUNE, PTGFRN, PTPRT, RAP2C, RHOJ, RIMS3, RMND5A, RNF111, RP2, RTF1, SACM1L, SACS, SCN2B, SGCD, SLC12A5, SLC36A1, SLC7A8, SMARCA5, SMC1A, SMOC2, SNX25, SOCS5, SRGAP3, SSX2IP, STXBP1, SYT1, SYT4, TAF4B, TLK1, TNFAIP8, TRAF3, TRAM1, TSC22D2, TSHZ2, TXNDC5, UBE2Q1, VAT1, ZNF248, ZNF395

OLIG3: AK2, ALAD, CREB3L2, CTNNA1, EFNA1, ERBB2IP, LMNA, OTUD7B, RALGDS, SH3PXD2B, SNAP23, STK3, VAMP3

UNK5: DYRK2, ELAVL2, GPR26, GSK3B, LRRTM4, NMT2, SMARCE1, UHMK1, WIPI2

OLIG1: AATK, ABI1, ADAM10, ADAMTS18, ADARB2, AGPS, ALCAM, AMOTL2, ANKRD13A, ARHGEF2, ATP11A, BACE1, C21orf91, CACNA1E, CAMKK2, CCNE2, CD46, CHD3, CLIC4, CLMN, CNP, CPEB2, CREB5, DDX17, DLGAP2, DOCK9, DPF3, ECHDC1, FAM107B, FAM19A4, FBN1, FBXL16, FBXL19, FBXL3, FLNB, FNBP1, GLDN, GPBP1L1, GPRC5B, HAPLN1, HIAT1, IPO13, JAKMIP2, KIF13B, KIF5C, KLF13, L3MBTL4, LAMP1, LDLRAP1, LZTS2, MAP1A, MAP7, MICAL3, MYO1D, NDE1, NDRG1, NFASC, NHLH2, NTAN1, PAK6, PCSK6, PDCD6IP, PDK3, PHIP, PHLDB1, PIGM, PIGZ, PKD2, PLEKHA6, PLXNA2, PRDM10, PSEN1, PTPRK, RAB5B, RAI14, REEP3, RNF44, S100PBP, SAR1B, SEMA6D, SERINC5, SH3BP4, SHANK2, SHANK3, SHB, SHC3, SLC20A2, SLC22A15, SLC31A2, SNX30, SNX7, SORT1, SPTLC2, TESK2, THBS2, TMEM63A, TNC, TNKS, TSPAN15, TTYH2, UBE3C, WSB1, XRN1, ZBED3, ZFYVE16, ZKSCAN1, ZNF407

miR‐9‐5p subset (497 genes): UNK1: ARCN1, ASXL1, BCLAF1, BRD4, BTBD7, CAP1, CBL, CBX5, CD47, CEP350, COG6, DHX40, DNAJC8, ENAH, EP400, FRMD4A, FXR1, FYTTD1, KCNK10, KIAA1549, KLF12, MAP3K3, MGA, MMP16, MTF2, NCOA3, NEK1, NUTF2, PCGF6, PGAP1, PHF20L1, PTMA, RCOR1, SAP30L, SEC23IP, SON, SPAG9, UBE2H, UBE3A, VGLL4, ZFP90, ZNF131, ZNF236, ZNF512

UNK5: DYRK2, ELAVL2, NMT2, SMARCE1, WIPI2

OLIG3: AK2, ALAD, CTNNA1, ERBB2IP, RALGDS, SH3PXD2B

MG3: CCDC50, CHSY1, CMTM6, KCTD12, TFRC, TGFBR1


17


We would like to note that due to a limited size of our sample under study we were a priori less likely to detect a true schizophrenia associated sub-module. This is unfortunately true for most currently available post-mortem data-sets in schizophrenia. New, yet to be published datasets will provide more power to unequivocally detect , schizophrenia associated sub-modules and we keep confident that these analyses will add further support to our finding. Furthermore we would like to note that post mortem expression analyses might not capture all of the differential expression relating to the neurodevelopmental role of miR-9-5p.


18


Determining if the targetome overlap between two miRNA is bigger than ex-pected by chance In the main text, we look at the intersections of the predicted targets for two pairs of miRNA – miR-9-5p com-pared to miR-137 and miR-2682-5p to miR-137 (eFigure 6) eFigure 6: Venn diagrams of the miR-9-5p/miR-137 and miR-137/-miR-2682-5p targetomes.

While analyzing the overlap in these two miRNA pairs we observed an unequal distribution in the number of miRNA targeting individual genes. We observed a tendency of genes to be targeted by either many miRNA or only one/a few. As a consequence genes targeted by multiple miRNA are more likely to appear in an overlap of the targetomes of two random miRNA. To establish if an overlap between the targetomes of two miRNA is big-ger than expected by chance, it therefore is indicated to take this observation into account. Ignoring this observa-tion and taking Fisher’s exact test (in case of small cell counts) or a chi-square test would likely lead to errone-ous associations. As an alternative, the following procedure was employed (detailed for the example overlap of miR-9-5p and miR-137):

A pool of genes comprising all conserved targets of all conserved miRNA-families was created. We did so add-ing for every occurrence of a target in a miRNA targetome one copy of this gene to the combined pool. As a consequence each gene was n times present in the pool with n being the number of miRNA-families targeting this gene. Please note that no copies were added to the pool for the miR-137 targetome. In a subsequent step we created r = 1000 replicate sets of miR-9-5p targetomes matching the original number of miR-9-5p targets (n=1237) as follows: for each replicate set we drew genes at random from the pool and added them to the repli-cate set if that gene wasn’t already in the replicate set. When the replicate set had the same number of (unique) genes as the original set we calculated the overlap with miR-137. For this we counted all instances p where the replicate sets had as large or a larger overlap with miR-137 as the original targetome of miR-9-5p and calculated the empirical p-value as the fraction p/r. Note that our procedure can be interpreted as weighed sampling.

We used the same principles to study the overlap between miR-137 and miR-2682-5p. However, for this analy-sis we used all TargetScan predictions regardless of conservation (see main text for details).

The results for the overlaps with miR-137 were: Equal or larger

overlap Less overlap Empirical

p‐value Chi‐square test p‐

value

miR‐9‐5p 277 723 0.28 < 2.2 x 10‐16

miR‐2682‐5p 310 690 0.31 < 2.2 x 10‐16

The vast incongruences between the empirical p-values and the chi-square test results are likely caused by the aforementioned unequal distribution in the number miRNA targeting a given gene. On average a random gene targeted by at least one miRNA are targeted by 6.5 miRNA, whereas the genes in the intersection of miR-137 and miR-9-5p on average are targeted by 20 miRNA. The fact that the two overlaps are non-significant does not preclude shared functions between the miRNA, but it indicates that further biological knowledge would be need-ed to establish it. It should be noted that we choose to study the overlap in targetomes of miR-9-5p and miR-137 based on our clustering results for these two miRNA targetomes (as part of the ten highest scoring miRNA gene sets, see Figure 2b and eFigure 2). It should also noted that the miR-2682-5p targetome likely has more false predictions due to the inclusion of non-conserved targets.


19


A note on the limited support for an association of the miR-130b and miR-193a-3p targetomes As detailed in the main text, imprecision in target prediction is a limitation to our study. This might be one of the reasons why our study only found modest evidence for association with miR-130b, a miRNA previously impli-cated with schizophrenia16. Another reason might the sample size of the PGC2 study. While sufficiently powered to detect association with 108 schizophrenia loci it still lacks power to detect all disease-associated variants at reasonable significance levels17. Both reasons could potentially also underlie the complete lack of evidence for association for miR-193a-3p, the second miRNA implicated in the aforementioned study16.

TargetScan gene sets (Main analysis, R2=0.6, 500kb)

p‐value @1E‐5

Corrected p‐value @top1%

p‐value @top5%

Score

Size

Brain

p‐value @1E‐5

Raw p‐value @top1%

p‐value @top5%

miR‐130ab‐3p/301a‐3p/301b/ 454‐3p/3666/4295

1 0.0980 0.1700 9 899 76% 0.1260 0.0010 0.0017

miR‐193ab‐3p 1 1 1 1 222 79% 0.2569 0.4586 0.1069

The three different thresholds represent the different significance thresholds for the index-SNP used during the clumping procedures. Top-1% of SNPs have p-values less than 3.420 x 10-4, top 5% of SNPs have p-values less than 1.096 x 10-2. For a detailed description of the “Score” column please refer to the main text. “Size” indicates the number of genes in the gene set. “Brain” indicates the percentage of genes in the targetomes expressed in the brain. ”Corrected” are the p-values after correcting for multiple testing of all conserved miRNA families, where-as “Raw” are the unadjusted p-values. miRNAs are ranked by their Score.


20


eReferences 1. Duursma AM, Kedde M, Schrier M, le Sage C, Agami R. miR-148 targets human DNMT3b

protein coding region. Rna. 2008;14(5):872-877. 2. Forman JJ, Legesse-Miller A, Coller HA. A search for conserved sequences in coding regions

reveals that the let-7 microRNA targets Dicer within its coding sequence. Proceedings of the National Academy of Sciences of the United States of America. 2008;105(39):14879-14884.

3. Helwak A, Kudla G, Dudnakova T, Tollervey D. Mapping the human miRNA interactome by CLASH reveals frequent noncanonical binding. Cell. 2013;153(3):654-665.

4. Bandyopadhyay S, Mitra R. TargetMiner: microRNA target prediction with systematic identification of tissue-specific negative examples. Bioinformatics. 2009;25(20):2625-2631.

5. Betel D, Koppal A, Agius P, Sander C, Leslie C. Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites. Genome biology. 2010;11(8):R90.

6. Li JH, Liu S, Zhou H, Qu LH, Yang JH. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic acids research. 2014;42(Database issue):D92-97.

7. Boudreau RL, Jiang P, Gilmore BL, et al. Transcriptome-wide discovery of microRNA binding sites in human brain. Neuron. 2014;81(2):294-305.

8. Balakrishnan I, Yang X, Brown J, et al. Genome‐Wide Analysis of miRNA‐mRNA Interactions in Marrow Stromal Cells. Stem Cells. 2014;32(3):662-673.

9. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014;511(7510):421-427.

10. Perry JR, Day F, Elks CE, et al. Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. Nature. 2014;514(7520):92-97.

11. Jostins L, Ripke S, Weersma RK, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature. 2012;491(7422):119-124.

12. Wood AR, Esko T, Yang J, et al. Defining the role of common variation in the genomic and biological architecture of adult human height. Nature genetics. 2014;46(11):1173-1186.

13. BrainSpan: Atlas of the Developing Human Brain. 2011; Funded by ARRA Awards 1RC2MH089921-089901, 089921RC089922MH090047-089901, and 089921RC089922MH089929-089901. Available at: http://brainspan.org. Accessed 17 Jun, 2014.

14. Barshir R, Basha O, Eluk A, Smoly IY, Lan A, Yeger-Lotem E. The TissueNet database of human tissue protein–protein interactions. Nucleic acids research. 2013;41(D1):D841-D844.

15. Roussos P, Katsel P, Davis KL, Siever LJ, Haroutunian V. A system-level transcriptomic analysis of schizophrenia using postmortem brain tissue samples. Archives of general psychiatry. 2012;69(12):1205-1213.

16. Wei H, Yuan Y, Liu S, et al. Detection of Circulating miRNA Levels in Schizophrenia. American Journal of Psychiatry. 2015:appi. ajp. 2015.14030273.

17. Ripke S, O'Dushlaine C, Chambert K, et al. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nature genetics. 2013;45(10):1150-1159.


21


eTable 1: Full results of the TargetScan conserved miRNA gene set analysis. The three different thresholds represent the different significance thresholds for the index-SNP used during the clumping procedures. Top-1% of SNPs have p-values less than 3.420 x 10-4, top 5% of SNPs have p-values less than 1.096 x 10-2. For a detailed description of the “Score” column please refer to the main text. “Size” indicates the number of genes in the gene set. “Brain” indicates the per-centage of genes in the targetomes expressed in the brain. ”Corrected” are the p-values after correct-ing for multiple testing, whereas “Raw” are the unadjusted p-values. miRNAs are ranked by their Score. miRNA with less than 50 targets were not included in our tests and therefore the p-values are marked with “NA” instead.


p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

miR‐9‐5p 3.8E‐02 5.6E‐03 8.8E‐04 212 1237 75% 3.9E‐04 4.9E‐05 1.3E‐06

miR‐485‐5p 1.5E‐01 1.4E‐01 1.1E‐03 68 379 73% 1.7E‐03 1.4E‐03 3.8E‐06

miR‐137 8.4E‐02 3.3E‐02 3.2E‐02 68 1144 77% 9.2E‐04 3.0E‐04 2.9E‐04

miR‐101‐3p 2.4E‐01 1.3E‐02 2.1E‐02 63 803 78% 2.9E‐03 1.2E‐04 1.8E‐04

miR‐200bc‐3p/429 1.0E+00 5.0E‐03 1.1E‐03 50 1057 77% 2.0E‐01 4.4E‐05 3.8E‐06

miR‐7‐5p 4.3E‐01 5.6E‐02 2.4E‐02 34 444 73% 6.6E‐03 5.2E‐04 2.1E‐04

miR‐1/206/613 2.1E‐01 3.8E‐01 5.2E‐03 31 787 76% 2.6E‐03 5.1E‐03 4.3E‐05

miR‐374ab‐5p 9.0E‐01 7.5E‐03 3.0E‐02 29 678 72% 3.4E‐02 6.5E‐05 2.7E‐04

miR‐28‐5p/708‐5p/3139 7.2E‐02 3.8E‐02 4.2E‐01 29 209 80% 8.0E‐04 3.6E‐04 5.6E‐03

miR‐34ac‐5p/449b‐5p/449a 2.0E‐01 2.1E‐01 7.9E‐02 24 655 78% 2.4E‐03 2.4E‐03 7.6E‐04

miR‐125ab‐5p/4319 5.2E‐01 4.8E‐01 8.8E‐04 23 847 75% 9.0E‐03 7.2E‐03 1.3E‐06

miR‐300/381‐3p 9.9E‐01 4.3E‐02 2.4E‐02 20 881 78% 7.7E‐02 4.1E‐04 2.1E‐04

miR‐132‐3p/212‐3p 7.4E‐01 1.5E‐02 1.8E‐01 18 406 79% 1.8E‐02 1.4E‐04 1.9E‐03

miR‐27ab‐3p 1.0E+00 2.7E‐01 1.8E‐03 17 1212 74% 2.7E‐01 3.2E‐03 1.1E‐05

miR‐25‐3p/32‐5p/92ab‐3p/363‐3p/367‐3p 2.2E‐02 1.4E‐01 9.4E‐01 15 892 76% 2.2E‐04 1.4E‐03 4.1E‐02

miR‐425‐5p 8.3E‐02 4.1E‐02 9.5E‐01 15 211 75% 9.1E‐04 3.9E‐04 4.6E‐02

miR‐19ab‐3p 8.9E‐01 3.6E‐01 8.2E‐03 13 1167 75% 3.3E‐02 4.6E‐03 7.0E‐05

miR‐377‐3p 1.0E‐01 5.6E‐01 2.4E‐01 13 573 75% 1.1E‐03 9.4E‐03 2.6E‐03

miR‐138‐5p 2.1E‐01 3.2E‐02 9.0E‐01 13 560 77% 2.6E‐03 2.9E‐04 3.2E‐02

miR‐24‐3p 3.5E‐01 9.9E‐01 6.8E‐03 12 632 73% 5.0E‐03 7.7E‐02 5.6E‐05

miR‐128‐3p 9.9E‐01 6.5E‐01 1.1E‐03 11 1047 75% 9.2E‐02 1.2E‐02 3.8E‐06

miR‐153‐3p 9.9E‐01 6.0E‐01 3.2E‐03 10 748 72% 8.2E‐02 1.0E‐02 2.3E‐05

miR‐340‐5p 1.0E+00 8.3E‐01 8.8E‐04 10 1424 74% 3.3E‐01 2.2E‐02 1.3E‐06

miR‐130ab‐3p/301a‐3p/301b/ 454‐3p/3666/4295

1.0E+00 9.8E‐02 1.7E‐01 9 899 76% 1.3E‐01 1.0E‐03 1.7E‐03

miR‐370‐3p 1.0E+00 7.1E‐01 3.8E‐03 9 391 76% 5.3E‐01 1.5E‐02 2.9E‐05

miR‐342‐3p 1.0E+00 9.1E‐01 8.8E‐04 9 284 76% 2.3E‐01 3.3E‐02 1.3E‐06

miR‐124‐3p/506‐3p 9.3E‐01 9.8E‐01 9.5E‐04 9 1654 77% 3.9E‐02 6.0E‐02 2.5E‐06

miR‐218‐5p 7.6E‐01 7.5E‐01 1.6E‐02 9 931 75% 1.9E‐02 1.7E‐02 1.4E‐04

miR‐448 8.7E‐01 3.4E‐01 8.5E‐02 8 699 71% 3.0E‐02 4.3E‐03 8.2E‐04

miR‐17‐5p/20ab‐5p/93‐5p/106ab‐5p/ 519d‐3p

1.0E+00 9.3E‐01 1.4E‐03 8 1220 77% 7.2E‐01 3.8E‐02 7.5E‐06

miR‐376c‐3p 9.7E‐01 2.7E‐01 1.1E‐01 8 254 72% 5.9E‐02 3.2E‐03 1.1E‐03

miR‐181abcd‐5p/4262 4.7E‐01 7.5E‐01 1.1E‐01 7 1195 75% 7.8E‐03 1.7E‐02 1.1E‐03

miR‐149‐5p 1.0E+00 4.4E‐01 6.5E‐02 7 451 75% 1.5E‐01 6.2E‐03 6.0E‐04

miR‐326/330‐5p 8.1E‐01 2.0E‐01 3.3E‐01 7 444 75% 2.2E‐02 2.2E‐03 4.1E‐03

miR‐495‐3p 8.5E‐01 4.2E‐01 1.3E‐01 7 903 75% 2.8E‐02 5.9E‐03 1.2E‐03

miR‐31‐5p 9.7E‐01 1.8E‐01 2.5E‐01 7 368 71% 5.6E‐02 1.9E‐03 2.9E‐03

miR‐544a 1.0E+00 9.5E‐01 5.4E‐03 7 573 72% 2.6E‐01 4.3E‐02 4.4E‐05

miR‐302abcd‐3p/302e/372‐3p/ 373‐3p/520acd‐3p/520be

1.0E+00 7.1E‐01 2.7E‐02 6 844 74% 3.5E‐01 1.4E‐02 2.4E‐04

miR‐141‐3p/200a‐3p 9.6E‐01 4.3E‐01 1.2E‐01 6 744 76% 5.3E‐02 6.0E‐03 1.1E‐03

miR‐539‐5p 9.3E‐01 1.2E‐01 4.5E‐01 6 698 73% 3.9E‐02 1.2E‐03 6.4E‐03

miR‐197‐3p 8.9E‐01 1.5E‐01 4.5E‐01 6 219 71% 3.2E‐02 1.6E‐03 6.4E‐03

let‐7abcdefgi‐5p/98‐5p/4458/4500 1.0E+00 9.9E‐01 8.8E‐03 6 1072 73% 3.8E‐01 7.2E‐02 7.5E‐05

miR‐371a‐5p 1.0E+00 5.9E‐02 6.1E‐01 6 354 73% 2.7E‐01 5.6E‐04 1.1E‐02


22



p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

miR‐199ab‐5p 9.9E‐01 1.2E‐01 4.8E‐01 6 494 77% 7.3E‐02 1.1E‐03 7.1E‐03

miR‐410‐3p 8.7E‐01 5.1E‐01 1.6E‐01 5 636 76% 2.9E‐02 7.8E‐03 1.7E‐03

miR‐22‐3p 2.0E‐01 1.0E+00 3.8E‐01 5 507 72% 2.6E‐03 1.8E‐01 5.0E‐03

miR‐150‐5p 8.7E‐01 8.2E‐01 7.7E‐02 5 282 73% 3.0E‐02 2.1E‐02 7.2E‐04

miR‐30abcde‐5p 1.0E+00 9.2E‐01 3.0E‐02 5 1357 75% 2.9E‐01 3.4E‐02 2.7E‐04

miR‐491‐5p 1.0E+00 8.0E‐01 5.8E‐02 5 173 74% 2.0E‐01 2.0E‐02 5.3E‐04

miR‐23ab‐3p/23c 8.4E‐01 7.9E‐01 1.2E‐01 5 1125 72% 2.6E‐02 2.0E‐02 1.2E‐03

miR‐205‐5p 1.0E+00 7.4E‐01 8.5E‐02 5 417 76% 8.7E‐01 1.7E‐02 8.2E‐04

miR‐320abcd/4429 9.7E‐01 2.0E‐01 5.6E‐01 4 788 76% 5.9E‐02 2.2E‐03 9.3E‐03

miR‐224‐5p 7.6E‐01 1.0E+00 1.2E‐01 4 383 75% 1.9E‐02 1.1E‐01 1.2E‐03

miR‐29abc‐3p 1.0E+00 1.0E+00 5.6E‐02 4 1077 75% 8.1E‐01 5.7E‐01 5.2E‐04

miR‐144‐3p 9.7E‐01 9.3E‐01 9.3E‐02 4 878 76% 5.5E‐02 3.8E‐02 9.0E‐04

miR‐196ab‐5p 1.0E+00 1.0E+00 6.9E‐02 4 295 72% 3.7E‐01 2.6E‐01 6.3E‐04

miR‐496 9.8E‐01 9.2E‐02 1.0E+00 4 128 77% 6.0E‐02 8.9E‐04 3.3E‐01

miR‐133a‐3p/133b 1.0E+00 8.8E‐01 1.4E‐01 3 648 75% 1.3E‐01 2.8E‐02 1.5E‐03

miR‐204‐5p/211‐5p 5.7E‐01 7.6E‐01 5.4E‐01 3 670 76% 1.0E‐02 1.8E‐02 8.6E‐03

miR‐96‐5p/1271‐5p 1.0E+00 9.9E‐01 1.2E‐01 3 1049 75% 1.5E‐01 6.5E‐02 1.2E‐03

miR‐504‐5p/4725‐5p 1.0E+00 9.8E‐01 1.4E‐01 3 212 74% 2.3E‐01 6.0E‐02 1.4E‐03

miR‐145‐5p 1.0E+00 1.0E+00 1.4E‐01 3 730 74% 8.5E‐01 4.0E‐01 1.4E‐03

miR‐335‐5p 1.6E‐01 1.0E+00 9.9E‐01 3 256 74% 1.9E‐03 1.6E‐01 7.7E‐02

miR‐122‐5p 1.0E+00 2.3E‐01 9.3E‐01 3 172 79% 3.6E‐01 2.5E‐03 3.9E‐02

miR‐155‐5p 8.6E‐01 1.0E+00 2.7E‐01 3 439 76% 2.9E‐02 3.5E‐01 3.0E‐03

miR‐26ab‐5p/1297/4465 9.7E‐01 8.5E‐01 3.3E‐01 3 884 73% 5.8E‐02 2.5E‐02 4.0E‐03

miR‐874‐3p 1.0E+00 9.5E‐01 2.4E‐01 3 269 76% 3.8E‐01 4.4E‐02 2.8E‐03

miR‐194‐5p 1.0E+00 2.1E‐01 1.0E+00 3 367 80% 3.2E‐01 2.4E‐03 4.0E‐01

miR‐192‐5p/215‐5p 9.7E‐01 8.2E‐01 3.5E‐01 3 156 66% 5.6E‐02 2.2E‐02 4.5E‐03

miR‐382‐5p 8.4E‐01 3.2E‐01 1.0E+00 3 217 71% 2.6E‐02 3.9E‐03 4.3E‐01

miR‐543 1.0E+00 9.0E‐01 2.9E‐01 3 737 75% 9.8E‐02 3.1E‐02 3.4E‐03

miR‐494‐3p 1.0E+00 7.5E‐01 4.0E‐01 3 574 74% 9.9E‐02 1.7E‐02 5.3E‐03

miR‐135ab‐5p 8.8E‐01 6.2E‐01 6.5E‐01 2 716 75% 3.0E‐02 1.1E‐02 1.2E‐02

miR‐182‐5p 9.8E‐01 6.3E‐01 5.5E‐01 2 1122 73% 6.3E‐02 1.2E‐02 8.8E‐03

miR‐146ab‐5p 1.0E+00 5.0E‐01 7.0E‐01 2 225 74% 1.8E‐01 7.7E‐03 1.5E‐02

miR‐590‐3p 1.0E+00 9.9E‐01 3.1E‐01 2 1250 72% 7.5E‐01 6.6E‐02 3.8E‐03

miR‐191‐5p 6.8E‐01 1.0E+00 6.1E‐01 2 54 78% 1.4E‐02 8.9E‐02 1.1E‐02

miR‐142‐3p 1.0E+00 5.8E‐01 7.5E‐01 2 331 75% 1.1E‐01 9.7E‐03 1.7E‐02

miR‐186‐5p 9.9E‐01 4.3E‐01 9.4E‐01 2 859 71% 7.1E‐02 6.0E‐03 4.0E‐02

miR‐339‐5p 1.0E+00 9.7E‐01 4.2E‐01 2 185 75% 1.3E‐01 5.0E‐02 5.8E‐03

miR‐542‐3p 1.0E+00 4.1E‐01 1.0E+00 2 279 74% 9.4E‐02 5.6E‐03 3.4E‐01

miR‐338‐3p 1.0E+00 1.0E+00 4.1E‐01 2 311 73% 5.5E‐01 1.3E‐01 5.5E‐03

miR‐148ab‐3p/152‐3p 9.9E‐01 4.8E‐01 9.5E‐01 2 697 77% 7.3E‐02 6.9E‐03 4.4E‐02

miR‐486‐5p 1.0E+00 1.0E+00 4.5E‐01 2 154 76% 1.2E‐01 4.7E‐01 6.3E‐03

miR‐499a‐5p 8.4E‐01 9.9E‐01 6.4E‐01 2 340 74% 2.6E‐02 8.1E‐02 1.2E‐02

miR‐129‐5p 1.0E+00 1.0E+00 5.2E‐01 2 544 75% 1.6E‐01 1.6E‐01 8.2E‐03

miR‐202‐3p 1.0E+00 1.0E+00 5.3E‐01 2 798 72% 5.0E‐01 1.1E‐01 8.4E‐03

miR‐216a‐5p 1.0E+00 9.2E‐01 6.2E‐01 2 287 73% 2.8E‐01 3.5E‐02 1.1E‐02

miR‐505‐3p 1.0E+00 9.8E‐01 5.9E‐01 2 236 73% 3.9E‐01 6.1E‐02 1.0E‐02

miR‐328‐3p 1.0E+00 1.0E+00 5.8E‐01 2 209 76% 7.3E‐01 1.3E‐01 9.7E‐03

miR‐384 9.9E‐01 9.6E‐01 6.6E‐01 2 302 78% 8.6E‐02 4.6E‐02 1.3E‐02

miR‐154‐5p 9.6E‐01 1.0E+00 6.7E‐01 2 129 77% 5.2E‐02 1.0E‐01 1.3E‐02

miR‐185‐5p/4306/4644 1.0E+00 1.0E+00 6.4E‐01 2 320 68% 1.8E‐01 1.1E‐01 1.2E‐02

miR‐143‐3p/4770 1.0E+00 7.7E‐01 8.9E‐01 1 407 73% 2.0E‐01 1.8E‐02 3.0E‐02

miR‐873‐5p 1.0E+00 1.0E+00 6.9E‐01 1 335 70% 3.8E‐01 4.2E‐01 1.4E‐02

miR‐15ab‐5p/16‐5p/195‐5p/424‐5p/497‐5p 1.0E+00 1.0E+00 7.0E‐01 1 1275 74% 2.4E‐01 1.1E‐01 1.4E‐02

miR‐876‐5p/3167 7.7E‐01 9.7E‐01 9.6E‐01 1 268 66% 2.0E‐02 5.2E‐02 4.7E‐02

miR‐203a 1.0E+00 1.0E+00 7.0E‐01 1 867 74% 2.8E‐01 2.1E‐01 1.5E‐02

miR‐223‐3p 1.0E+00 8.4E‐01 8.7E‐01 1 311 76% 1.7E‐01 2.4E‐02 2.7E‐02


23



p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

miR‐299‐3p 1.0E+00 1.0E+00 7.2E‐01 1 91 80% 9.5E‐02 1.5E‐01 1.6E‐02

miR‐365a‐3p 8.9E‐01 8.8E‐01 1.0E+00 1 277 78% 3.2E‐02 2.8E‐02 1.4E‐01

miR‐216b‐5p 9.9E‐01 7.8E‐01 1.0E+00 1 290 73% 9.0E‐02 1.9E‐02 1.5E‐01

miR‐139‐5p 1.0E+00 7.7E‐01 1.0E+00 1 349 77% 2.0E‐01 1.8E‐02 2.2E‐01

miR‐329‐3p/362‐3p 1.0E+00 9.3E‐01 8.4E‐01 1 314 73% 1.4E‐01 3.8E‐02 2.4E‐02

miR‐208ab‐3p 1.0E+00 1.0E+00 7.8E‐01 1 182 70% 1.1E‐01 1.8E‐01 1.9E‐02

miR‐221‐3p/222‐3p 1.0E+00 9.2E‐01 9.0E‐01 1 444 76% 3.1E‐01 3.4E‐02 3.2E‐02

miR‐219a‐5p/4782‐3p 1.0E+00 1.0E+00 8.7E‐01 1 391 76% 5.3E‐01 1.4E‐01 2.8E‐02

miR‐324‐5p 1.0E+00 9.9E‐01 8.8E‐01 1 141 71% 7.3E‐01 8.1E‐02 2.9E‐02

miR‐421 1.0E+00 9.8E‐01 9.1E‐01 1 433 77% 2.2E‐01 5.9E‐02 3.3E‐02

miR‐653‐5p 1.0E+00 1.0E+00 8.9E‐01 1 224 72% 1.4E‐01 3.9E‐01 3.0E‐02

miR‐103a‐3p/107 1.0E+00 1.0E+00 9.0E‐01 1 650 76% 1.6E‐01 4.6E‐01 3.2E‐02

miR‐599 9.8E‐01 9.2E‐01 1.0E+00 1 209 71% 6.6E‐02 3.6E‐02 2.7E‐01

miR‐33ab‐5p 1.0E+00 9.2E‐01 9.9E‐01 1 415 76% 1.3E‐01 3.5E‐02 7.2E‐02

miR‐21‐5p/590‐5p 9.3E‐01 1.0E+00 1.0E+00 1 308 75% 3.9E‐02 1.4E‐01 1.0E‐01

miR‐488‐3p 1.0E+00 9.9E‐01 9.5E‐01 1 384 71% 8.4E‐01 6.9E‐02 4.5E‐02

miR‐490‐3p 1.0E+00 1.0E+00 9.6E‐01 1 192 72% 4.8E‐01 1.2E‐01 4.7E‐02

miR‐217 1.0E+00 9.6E‐01 1.0E+00 1 345 77% 1.4E‐01 4.6E‐02 1.9E‐01

miR‐214‐3p/761/3619‐5p 9.9E‐01 1.0E+00 9.7E‐01 1 678 77% 8.4E‐02 9.2E‐02 5.8E‐02

miR‐190a‐5p/190b 9.6E‐01 1.0E+00 1.0E+00 1 185 71% 5.3E‐02 1.7E‐01 5.0E‐01

miR‐183‐5p 1.0E+00 9.7E‐01 1.0E+00 1 386 78% 2.2E‐01 5.4E‐02 4.1E‐01

miR‐383‐5p 1.0E+00 1.0E+00 9.7E‐01 1 176 75% 2.7E‐01 3.0E‐01 5.7E‐02

miR‐125a‐3p 9.8E‐01 1.0E+00 1.0E+00 1 223 72% 6.0E‐02 2.4E‐01 2.1E‐01

miR‐361‐5p 1.0E+00 1.0E+00 9.9E‐01 1 240 69% 1.8E‐01 1.1E‐01 7.5E‐02

miR‐375 1.0E+00 1.0E+00 9.9E‐01 1 229 76% 9.4E‐01 3.2E‐01 7.5E‐02

miR‐503‐5p 9.9E‐01 1.0E+00 1.0E+00 1 387 75% 9.1E‐02 1.0E‐01 1.3E‐01

miR‐433‐3p 1.0E+00 1.0E+00 9.9E‐01 1 321 75% 1.6E‐01 9.6E‐02 9.1E‐02

miR‐346 1.0E+00 1.0E+00 9.9E‐01 1 143 74% 1.8E‐01 1.6E‐01 8.0E‐02

miR‐10ab‐5p 1.0E+00 1.0E+00 9.9E‐01 1 272 74% 7.0E‐01 2.5E‐01 8.0E‐02

miR‐136‐5p 1.0E+00 1.0E+00 9.9E‐01 1 272 67% 3.7E‐01 1.6E‐01 8.6E‐02

miR‐378a‐3p/378bcdefhi/422a 9.9E‐01 1.0E+00 1.0E+00 1 191 73% 9.1E‐02 1.4E‐01 5.3E‐01

miR‐296‐3p 1.0E+00 1.0E+00 1.0E+00 1 66 69% 1.8E‐01 9.9E‐02 1.2E‐01

miR‐193ab‐3p 1.0E+00 1.0E+00 1.0E+00 1 222 79% 2.6E‐01 4.6E‐01 1.1E‐01

miR‐99ab‐5p/100‐5p 1.0E+00 1.0E+00 1.0E+00 1 56 86% 7.3E‐01 1.1E‐01 5.0E‐01

miR‐379‐5p/3529‐5p 1.0E+00 1.0E+00 1.0E+00 1 93 66% 7.2E‐01 4.2E‐01 1.3E‐01

miR‐134‐5p/3118 1.0E+00 1.0E+00 1.0E+00 1 171 75% 3.2E‐01 1.5E‐01 2.4E‐01

miR‐455‐5p 1.0E+00 1.0E+00 1.0E+00 1 198 77% 7.3E‐01 7.8E‐01 1.6E‐01

miR‐18ab‐5p/4735‐3p 1.0E+00 1.0E+00 1.0E+00 1 275 73% 6.7E‐01 1.8E‐01 1.7E‐01

miR‐411‐5p 1.0E+00 1.0E+00 1.0E+00 1 106 78% 9.0E‐01 2.0E‐01 2.7E‐01

miR‐875‐5p 1.0E+00 1.0E+00 1.0E+00 1 110 81% 2.6E‐01 2.2E‐01 4.4E‐01

miR‐758‐3p 1.0E+00 1.0E+00 1.0E+00 1 235 71% 9.6E‐01 9.7E‐01 6.9E‐01

miR‐431‐5p 1.0E+00 1.0E+00 1.0E+00 1 167 75% 3.7E‐01 7.3E‐01 3.0E‐01

miR‐376ab‐3p 1.0E+00 1.0E+00 1.0E+00 1 214 75% 4.5E‐01 7.3E‐01 3.4E‐01

miR‐140‐5p 1.0E+00 1.0E+00 1.0E+00 1 345 77% 3.4E‐01 6.6E‐01 3.7E‐01

miR‐615‐3p NA NA NA 1 11 70% NA NA NA

miR‐551b‐3p/551a NA NA NA 1 8 75% NA NA NA

miR‐487b‐3p NA NA NA 1 14 86% NA NA NA

miR‐451a NA NA NA 1 20 68% NA NA NA

miR‐450a‐5p NA NA NA 1 10 80% NA NA NA



miR‐184 NA NA NA 1 28 85% NA NA NA




24


eTable 2: Alternative TargetScan gene set analysis: longer clumping range. These are the results of the main gene set analysis (eTable 1) with the change that the clumping range was increased to 3000 kb.

TargetScan gene sets (Alternative analysis, R2=0.6, 3000kb)

p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

miR‐9‐5p 3.8E‐02 6.3E‐03 8.1E‐04 211 1237 75% 3.9E‐04 5.6E‐05 1.3E‐06

miR‐137 8.3E‐02 3.1E‐02 1.5E‐02 81 1144 77% 8.9E‐04 2.9E‐04 1.3E‐04

miR‐101‐3p 2.2E‐01 8.9E‐03 2.2E‐02 69 803 78% 2.8E‐03 8.4E‐05 1.9E‐04

miR‐485‐5p 1.4E‐01 1.8E‐01 1.0E‐03 64 379 73% 1.6E‐03 1.9E‐03 3.8E‐06

miR‐200bc‐3p/429 1.0E+00 7.6E‐03 1.0E‐03 46 1057 77% 1.9E‐01 6.9E‐05 3.8E‐06

miR‐7‐5p 4.2E‐01 5.7E‐02 8.3E‐03 42 444 73% 6.3E‐03 5.4E‐04 6.7E‐05

miR‐1/206/613 2.0E‐01 3.6E‐01 3.8E‐03 35 787 76% 2.5E‐03 4.6E‐03 2.9E‐05

miR‐300/381‐3p 9.9E‐01 1.0E‐02 8.7E‐03 33 881 78% 7.8E‐02 9.1E‐05 7.1E‐05

miR‐374ab‐5p 8.9E‐01 8.8E‐03 3.2E‐02 29 678 71% 3.2E‐02 8.2E‐05 2.8E‐04

miR‐28‐5p/708‐5p/3139 7.4E‐02 4.1E‐02 4.2E‐01 28 209 80% 7.9E‐04 3.9E‐04 5.8E‐03

miR‐125ab‐5p/4319 5.3E‐01 4.2E‐01 8.1E‐04 25 847 75% 9.2E‐03 5.9E‐03 1.3E‐06

miR‐132‐3p/212‐3p 7.5E‐01 1.5E‐02 1.0E‐01 22 406 79% 1.9E‐02 1.4E‐04 9.5E‐04


miR‐27ab‐3p 1.0E+00 2.3E‐01 1.3E‐03 19 1212 74% 2.7E‐01 2.6E‐03 6.2E‐06

miR‐377‐3p 9.6E‐02 6.5E‐01 1.2E‐01 15 573 75% 1.0E‐03 1.2E‐02 1.2E‐03


miR‐425‐5p 8.9E‐02 5.3E‐02 9.5E‐01 14 211 75% 9.6E‐04 5.0E‐04 4.3E‐02

miR‐128‐3p 9.9E‐01 4.6E‐01 1.3E‐03 14 1047 75% 9.4E‐02 6.6E‐03 6.2E‐06

miR‐24‐3p 3.5E‐01 9.9E‐01 4.9E‐03 13 632 73% 4.9E‐03 7.7E‐02 3.9E‐05

miR‐19ab‐3p 9.1E‐01 4.6E‐01 5.5E‐03 12 1167 75% 3.5E‐02 6.6E‐03 4.2E‐05

miR‐138‐5p 2.0E‐01 5.6E‐02 8.9E‐01 11 560 77% 2.4E‐03 5.3E‐04 3.0E‐02

miR‐218‐5p 7.6E‐01 6.5E‐01 7.1E‐03 11 931 75% 1.9E‐02 1.2E‐02 5.6E‐05

miR‐340‐5p 1.0E+00 7.5E‐01 9.3E‐04 10 1424 74% 3.2E‐01 1.7E‐02 2.5E‐06

miR‐153‐3p 9.9E‐01 6.9E‐01 2.1E‐03 10 748 72% 7.9E‐02 1.4E‐02 1.4E‐05

miR‐495‐3p 8.5E‐01 2.7E‐01 7.3E‐02 10 903 75% 2.8E‐02 3.1E‐03 6.8E‐04

miR‐130ab‐3p/301a‐3p/301b/ 454‐3p/3666/4295

1.0E+00 1.2E‐01 1.3E‐01 9 899 76% 1.3E‐01 1.2E‐03 1.4E‐03

miR‐370‐3p 1.0E+00 7.2E‐01 2.6E‐03 9 391 76% 5.3E‐01 1.6E‐02 1.9E‐05

miR‐376c‐3p 9.7E‐01 1.8E‐01 1.1E‐01 9 254 72% 5.7E‐02 1.9E‐03 1.1E‐03

miR‐124‐3p/506‐3p 9.3E‐01 9.8E‐01 8.1E‐04 9 1654 77% 3.8E‐02 6.3E‐02 1.3E‐06

miR‐371a‐5p 1.0E+00 2.0E‐02 4.5E‐01 9 354 73% 2.7E‐01 1.9E‐04 6.3E‐03

miR‐448 8.6E‐01 3.6E‐01 6.4E‐02 9 699 71% 2.8E‐02 4.6E‐03 5.9E‐04

miR‐342‐3p 1.0E+00 9.7E‐01 8.1E‐04 8 284 76% 2.3E‐01 5.5E‐02 1.3E‐06

miR‐17‐5p/20ab‐5p/93‐5p/106ab‐5p/ 519d‐3p

1.0E+00 9.4E‐01 1.3E‐03 8 1220 77% 7.2E‐01 4.0E‐02 6.2E‐06

miR‐326/330‐5p 7.9E‐01 2.1E‐01 2.5E‐01 7 444 75% 2.1E‐02 2.3E‐03 2.9E‐03

miR‐544a 1.0E+00 9.2E‐01 3.0E‐03 7 573 72% 2.5E‐01 3.4E‐02 2.1E‐05

miR‐410‐3p 8.7E‐01 3.7E‐01 1.2E‐01 7 636 76% 3.0E‐02 4.8E‐03 1.2E‐03

miR‐181abcd‐5p/4262 4.7E‐01 9.1E‐01 7.3E‐02 7 1195 75% 7.8E‐03 3.3E‐02 6.8E‐04

miR‐150‐5p 8.7E‐01 5.4E‐01 8.5E‐02 6 282 73% 2.9E‐02 8.7E‐03 8.1E‐04

miR‐31‐5p 9.7E‐01 2.2E‐01 2.5E‐01 6 368 71% 5.6E‐02 2.4E‐03 2.8E‐03

miR‐141‐3p/200a‐3p 9.6E‐01 4.7E‐01 9.4E‐02 6 744 76% 5.3E‐02 6.9E‐03 9.0E‐04


1.0E+00 8.0E‐01 1.9E‐02 6 844 74% 3.5E‐01 2.0E‐02 1.6E‐04

let‐7abcdefgi‐5p/98‐5p/4458/4500 1.0E+00 1.0E+00 8.3E‐03 6 1072 73% 3.8E‐01 8.8E‐02 6.7E‐05

miR‐199ab‐5p 9.9E‐01 1.6E‐01 3.9E‐01 6 494 77% 7.1E‐02 1.8E‐03 5.1E‐03

miR‐149‐5p 1.0E+00 5.6E‐01 8.0E‐02 6 451 75% 1.5E‐01 9.2E‐03 7.6E‐04

miR‐197‐3p 8.9E‐01 1.7E‐01 4.7E‐01 5 219 71% 3.3E‐02 1.8E‐03 7.0E‐03

miR‐539‐5p 9.3E‐01 1.3E‐01 5.5E‐01 5 698 73% 3.9E‐02 1.4E‐03 8.9E‐03

miR‐23ab‐3p/23c 8.4E‐01 8.8E‐01 6.5E‐02 5 1125 72% 2.6E‐02 2.9E‐02 6.0E‐04

miR‐22‐3p 2.0E‐01 1.0E+00 4.1E‐01 5 507 71% 2.5E‐03 1.7E‐01 5.5E‐03



25



p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

miR‐224‐5p 7.5E‐01 1.0E+00 8.6E‐02 4 383 75% 1.8E‐02 1.2E‐01 8.2E‐04

miR‐320abcd/4429 9.8E‐01 2.0E‐01 5.2E‐01 4 788 76% 6.1E‐02 2.2E‐03 8.2E‐03

miR‐144‐3p 9.6E‐01 8.7E‐01 7.2E‐02 4 878 76% 5.4E‐02 2.7E‐02 6.7E‐04

miR‐491‐5p 1.0E+00 8.7E‐01 6.2E‐02 4 173 74% 2.0E‐01 2.8E‐02 5.7E‐04

miR‐204‐5p/211‐5p 5.6E‐01 6.7E‐01 4.1E‐01 4 670 76% 9.9E‐03 1.3E‐02 5.5E‐03

miR‐196ab‐5p 1.0E+00 1.0E+00 4.4E‐02 4 295 72% 3.8E‐01 2.9E‐01 3.9E‐04

miR‐494‐3p 1.0E+00 6.0E‐01 1.8E‐01 4 574 74% 9.7E‐02 1.1E‐02 1.9E‐03

miR‐205‐5p 1.0E+00 8.7E‐01 9.2E‐02 4 417 76% 8.7E‐01 2.7E‐02 8.9E‐04

miR‐29abc‐3p 1.0E+00 1.0E+00 6.9E‐02 4 1077 75% 8.1E‐01 5.1E‐01 6.4E‐04

miR‐135ab‐5p 8.7E‐01 5.7E‐01 3.6E‐01 4 716 75% 2.9E‐02 9.4E‐03 4.6E‐03

miR‐496 9.7E‐01 1.0E‐01 1.0E+00 3 128 77% 5.8E‐02 1.0E‐03 3.4E‐01

miR‐133a‐3p/133b 1.0E+00 9.0E‐01 1.3E‐01 3 648 75% 1.4E‐01 3.1E‐02 1.3E‐03

miR‐145‐5p 1.0E+00 1.0E+00 9.9E‐02 3 730 74% 8.4E‐01 4.1E‐01 9.4E‐04

miR‐96‐5p/1271‐5p 1.0E+00 9.9E‐01 1.2E‐01 3 1049 75% 1.5E‐01 7.0E‐02 1.2E‐03

miR‐382‐5p 8.4E‐01 2.0E‐01 1.0E+00 3 217 71% 2.6E‐02 2.2E‐03 4.4E‐01

miR‐504‐5p/4725‐5p 1.0E+00 9.9E‐01 1.5E‐01 3 212 74% 2.4E‐01 6.9E‐02 1.5E‐03

miR‐155‐5p 8.4E‐01 1.0E+00 2.2E‐01 3 439 76% 2.7E‐02 3.2E‐01 2.4E‐03

miR‐335‐5p 1.7E‐01 1.0E+00 9.5E‐01 3 256 74% 2.0E‐03 1.9E‐01 4.5E‐02

miR‐874‐3p 1.0E+00 9.6E‐01 2.0E‐01 3 269 76% 3.8E‐01 4.8E‐02 2.1E‐03

miR‐122‐5p 1.0E+00 2.2E‐01 9.3E‐01 3 172 79% 3.6E‐01 2.4E‐03 3.9E‐02

miR‐182‐5p 9.8E‐01 6.0E‐01 4.8E‐01 3 1122 73% 6.6E‐02 1.1E‐02 7.1E‐03

miR‐543 1.0E+00 9.0E‐01 2.7E‐01 3 737 75% 9.7E‐02 3.1E‐02 3.1E‐03

miR‐194‐5p 1.0E+00 2.5E‐01 1.0E+00 2 367 80% 3.2E‐01 2.8E‐03 4.4E‐01

miR‐590‐3p 1.0E+00 9.6E‐01 2.7E‐01 2 1250 72% 7.4E‐01 4.8E‐02 3.2E‐03

miR‐192‐5p/215‐5p 9.7E‐01 8.8E‐01 3.7E‐01 2 156 66% 5.8E‐02 2.8E‐02 4.7E‐03

miR‐216a‐5p 1.0E+00 8.9E‐01 3.4E‐01 2 287 73% 2.8E‐01 3.0E‐02 4.4E‐03

miR‐542‐3p 9.9E‐01 2.9E‐01 1.0E+00 2 279 74% 9.3E‐02 3.6E‐03 3.5E‐01

miR‐148ab‐3p/152‐3p 9.9E‐01 4.0E‐01 9.1E‐01 2 697 77% 7.3E‐02 5.5E‐03 3.4E‐02

miR‐26ab‐5p/1297/4465 9.8E‐01 8.9E‐01 4.2E‐01 2 884 73% 6.1E‐02 3.1E‐02 5.8E‐03

miR‐186‐5p 9.9E‐01 4.8E‐01 8.3E‐01 2 859 71% 7.1E‐02 7.0E‐03 2.3E‐02

miR‐191‐5p 6.7E‐01 9.9E‐01 6.3E‐01 2 54 78% 1.4E‐02 8.6E‐02 1.1E‐02

miR‐203a 1.0E+00 1.0E+00 3.7E‐01 2 867 74% 2.8E‐01 2.0E‐01 4.9E‐03

miR‐338‐3p 1.0E+00 1.0E+00 4.0E‐01 2 311 72% 5.5E‐01 1.2E‐01 5.4E‐03

miR‐339‐5p 1.0E+00 9.7E‐01 4.4E‐01 2 185 75% 1.3E‐01 5.3E‐02 6.2E‐03

miR‐146ab‐5p 1.0E+00 6.0E‐01 8.1E‐01 2 225 74% 1.8E‐01 1.1E‐02 2.1E‐02

miR‐486‐5p 1.0E+00 1.0E+00 4.5E‐01 2 154 76% 1.1E‐01 4.6E‐01 6.4E‐03

miR‐129‐5p 1.0E+00 1.0E+00 4.9E‐01 2 544 75% 1.6E‐01 1.2E‐01 7.2E‐03

miR‐15ab‐5p/16‐5p/195‐5p/424‐5p/497‐5p 1.0E+00 1.0E+00 5.1E‐01 2 1275 74% 2.4E‐01 9.5E‐02 7.9E‐03

miR‐202‐3p 1.0E+00 9.9E‐01 5.4E‐01 2 798 72% 5.1E‐01 8.6E‐02 8.6E‐03

miR‐499a‐5p 8.3E‐01 9.9E‐01 7.0E‐01 2 340 74% 2.5E‐02 8.6E‐02 1.4E‐02

miR‐221‐3p/222‐3p 1.0E+00 8.9E‐01 6.4E‐01 2 444 76% 3.1E‐01 3.0E‐02 1.2E‐02

miR‐505‐3p 1.0E+00 9.9E‐01 5.8E‐01 2 236 73% 3.8E‐01 6.6E‐02 9.8E‐03

miR‐223‐3p 1.0E+00 7.7E‐01 8.1E‐01 2 311 76% 1.7E‐01 1.8E‐02 2.1E‐02

miR‐143‐3p/4770 1.0E+00 7.5E‐01 8.5E‐01 1 407 73% 2.0E‐01 1.7E‐02 2.5E‐02

miR‐185‐5p/4306/4644 1.0E+00 1.0E+00 6.1E‐01 1 320 68% 1.7E‐01 1.1E‐01 1.1E‐02

miR‐384 9.9E‐01 9.8E‐01 6.7E‐01 1 302 78% 8.8E‐02 5.6E‐02 1.3E‐02

miR‐154‐5p 9.7E‐01 1.0E+00 6.9E‐01 1 129 77% 5.5E‐02 1.2E‐01 1.4E‐02

miR‐873‐5p 1.0E+00 1.0E+00 6.7E‐01 1 335 70% 3.7E‐01 4.4E‐01 1.3E‐02

miR‐328‐3p 1.0E+00 1.0E+00 6.9E‐01 1 209 76% 7.3E‐01 1.3E‐01 1.4E‐02

miR‐876‐5p/3167 7.7E‐01 9.7E‐01 9.6E‐01 1 268 66% 2.0E‐02 5.3E‐02 4.8E‐02

miR‐142‐3p 1.0E+00 8.3E‐01 8.9E‐01 1 331 75% 1.1E‐01 2.3E‐02 3.1E‐02

miR‐365a‐3p 8.9E‐01 8.4E‐01 1.0E+00 1 277 78% 3.2E‐02 2.3E‐02 1.0E‐01

miR‐208ab‐3p 1.0E+00 1.0E+00 7.6E‐01 1 182 70% 1.1E‐01 1.8E‐01 1.8E‐02

miR‐299‐3p 1.0E+00 1.0E+00 7.7E‐01 1 91 80% 9.4E‐02 1.4E‐01 1.8E‐02

miR‐653‐5p 1.0E+00 1.0E+00 7.6E‐01 1 224 71% 1.4E‐01 3.3E‐01 1.8E‐02

miR‐421 1.0E+00 9.7E‐01 8.2E‐01 1 433 77% 2.3E‐01 5.0E‐02 2.2E‐02


26



p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

miR‐329‐3p/362‐3p 1.0E+00 9.5E‐01 8.5E‐01 1 314 73% 1.4E‐01 4.3E‐02 2.5E‐02

miR‐219a‐5p/4782‐3p 1.0E+00 1.0E+00 8.0E‐01 1 391 76% 5.2E‐01 1.1E‐01 2.1E‐02

miR‐216b‐5p 9.9E‐01 8.4E‐01 1.0E+00 1 290 73% 8.9E‐02 2.4E‐02 1.5E‐01

miR‐139‐5p 1.0E+00 8.5E‐01 1.0E+00 1 349 77% 2.0E‐01 2.5E‐02 3.0E‐01

miR‐488‐3p 1.0E+00 9.8E‐01 9.1E‐01 1 384 71% 8.4E‐01 6.4E‐02 3.3E‐02

miR‐324‐5p 1.0E+00 9.8E‐01 9.1E‐01 1 141 71% 7.2E‐01 6.0E‐02 3.4E‐02

miR‐490‐3p 1.0E+00 9.8E‐01 9.2E‐01 1 192 72% 4.8E‐01 6.3E‐02 3.5E‐02

miR‐599 9.8E‐01 9.2E‐01 1.0E+00 1 209 71% 6.9E‐02 3.5E‐02 2.0E‐01

miR‐33ab‐5p 1.0E+00 9.3E‐01 9.8E‐01 1 415 76% 1.2E‐01 3.7E‐02 6.4E‐02

miR‐103a‐3p/107 1.0E+00 1.0E+00 9.2E‐01 1 650 76% 1.6E‐01 4.9E‐01 3.6E‐02

miR‐21‐5p/590‐5p 9.3E‐01 1.0E+00 1.0E+00 1 308 75% 4.1E‐02 1.7E‐01 1.2E‐01

miR‐346 1.0E+00 1.0E+00 9.3E‐01 1 143 74% 1.8E‐01 1.1E‐01 3.9E‐02

miR‐383‐5p 1.0E+00 1.0E+00 9.4E‐01 1 176 75% 2.7E‐01 1.8E‐01 4.0E‐02

miR‐214‐3p/761/3619‐5p 1.0E+00 9.9E‐01 9.6E‐01 1 678 77% 1.2E‐01 8.1E‐02 4.9E‐02

miR‐361‐5p 1.0E+00 9.9E‐01 9.7E‐01 1 240 69% 1.7E‐01 7.0E‐02 5.8E‐02

miR‐190a‐5p/190b 9.7E‐01 1.0E+00 1.0E+00 1 185 71% 5.5E‐02 1.9E‐01 5.0E‐01

miR‐125a‐3p 9.8E‐01 1.0E+00 1.0E+00 1 223 72% 6.0E‐02 1.6E‐01 1.6E‐01

miR‐217 1.0E+00 9.8E‐01 1.0E+00 1 345 77% 1.5E‐01 5.8E‐02 2.3E‐01

miR‐433‐3p 1.0E+00 1.0E+00 9.9E‐01 1 321 75% 1.6E‐01 9.0E‐02 7.6E‐02

miR‐375 1.0E+00 1.0E+00 9.9E‐01 1 229 76% 9.4E‐01 3.4E‐01 7.4E‐02

miR‐183‐5p 1.0E+00 9.9E‐01 1.0E+00 1 386 78% 2.1E‐01 7.6E‐02 4.5E‐01

miR‐503‐5p 9.9E‐01 1.0E+00 1.0E+00 1 387 75% 9.2E‐02 1.3E‐01 1.1E‐01

miR‐10ab‐5p 1.0E+00 1.0E+00 9.9E‐01 1 272 74% 6.9E‐01 2.8E‐01 8.1E‐02

miR‐378a‐3p/378bcdefhi/422a 9.9E‐01 1.0E+00 1.0E+00 1 191 73% 9.3E‐02 1.1E‐01 4.9E‐01

miR‐193ab‐3p 1.0E+00 1.0E+00 1.0E+00 1 222 79% 2.6E‐01 4.9E‐01 1.1E‐01

miR‐136‐5p 1.0E+00 1.0E+00 1.0E+00 1 272 67% 3.7E‐01 1.9E‐01 1.1E‐01

miR‐296‐3p 1.0E+00 1.0E+00 1.0E+00 1 66 69% 1.8E‐01 1.7E‐01 1.2E‐01

miR‐99ab‐5p/100‐5p 1.0E+00 1.0E+00 1.0E+00 1 56 86% 7.3E‐01 1.2E‐01 5.0E‐01

miR‐379‐5p/3529‐5p 1.0E+00 1.0E+00 1.0E+00 1 93 66% 7.3E‐01 3.5E‐01 1.3E‐01

miR‐455‐5p 1.0E+00 1.0E+00 1.0E+00 1 198 77% 7.4E‐01 7.5E‐01 1.7E‐01

miR‐18ab‐5p/4735‐3p 1.0E+00 1.0E+00 1.0E+00 1 275 73% 6.8E‐01 2.3E‐01 2.0E‐01

miR‐411‐5p 1.0E+00 1.0E+00 1.0E+00 1 106 78% 9.0E‐01 2.0E‐01 2.6E‐01

miR‐134‐5p/3118 1.0E+00 1.0E+00 1.0E+00 1 171 75% 3.3E‐01 2.1E‐01 2.3E‐01

miR‐875‐5p 1.0E+00 1.0E+00 1.0E+00 1 110 81% 2.6E‐01 3.0E‐01 4.5E‐01

miR‐758‐3p 1.0E+00 1.0E+00 1.0E+00 1 235 70% 9.6E‐01 9.7E‐01 6.8E‐01

miR‐431‐5p 1.0E+00 1.0E+00 1.0E+00 1 167 75% 3.7E‐01 7.9E‐01 2.6E‐01

miR‐376ab‐3p 1.0E+00 1.0E+00 1.0E+00 1 214 75% 4.4E‐01 6.7E‐01 3.4E‐01

miR‐140‐5p 1.0E+00 1.0E+00 1.0E+00 1 345 77% 3.5E‐01 6.6E‐01 3.8E‐01












27


eTable 3: Alternative TargetScan gene set analysis: lower LD-threshold. These are the results of the main gene set analysis (eTable 1) with the change that the clumping LD threshold was lowered to 0.1.


p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

miR‐218‐5p 4.1E‐03 1.3E‐03 6.9E‐04 410 931 75% 3.8E‐05 1.0E‐05 1.3E‐06

miR‐137 2.3E‐02 5.8E‐04 6.9E‐04 333 1144 77% 2.3E‐04 1.3E‐06 1.3E‐06


miR‐9‐5p 3.7E‐02 6.4E‐04 6.9E‐04 296 1237 75% 3.8E‐04 2.5E‐06 1.3E‐06

miR‐204‐5p/211‐5p 3.4E‐02 1.6E‐03 6.9E‐04 270 670 76% 3.4E‐04 1.3E‐05 1.3E‐06


miR‐182‐5p 4.6E‐02 4.1E‐03 6.9E‐04 219 1122 73% 4.7E‐04 3.5E‐05 1.3E‐06

miR‐101‐3p 3.0E‐02 2.5E‐02 6.9E‐04 175 803 78% 3.1E‐04 2.3E‐04 1.3E‐06

miR‐19ab‐3p 1.5E‐01 4.7E‐03 6.9E‐04 153 1167 75% 1.7E‐03 4.0E‐05 1.3E‐06

miR‐7‐5p 7.8E‐02 1.4E‐02 9.8E‐04 149 444 73% 8.1E‐04 1.2E‐04 6.2E‐06

miR‐132‐3p/212‐3p 2.2E‐01 3.1E‐03 7.3E‐04 141 406 79% 2.6E‐03 2.6E‐05 2.5E‐06

miR‐128‐3p 2.9E‐01 3.0E‐03 6.9E‐04 126 1047 75% 3.7E‐03 2.5E‐05 1.3E‐06

miR‐141‐3p/200a‐3p 3.3E‐01 6.5E‐03 6.9E‐04 105 744 76% 4.5E‐03 5.6E‐05 1.3E‐06

miR‐138‐5p 6.0E‐03 3.4E‐01 1.3E‐03 98 560 77% 5.7E‐05 4.3E‐03 8.7E‐06

miR‐130ab‐3p/301a‐3p/301b/ 454‐3p/3666/4295

8.0E‐01 9.4E‐04 6.9E‐04 81 899 76% 2.1E‐02 6.2E‐06 1.3E‐06

miR‐374ab‐5p 8.9E‐01 6.4E‐04 6.9E‐04 77 678 71% 3.2E‐02 2.5E‐06 1.3E‐06

miR‐200bc‐3p/429 9.6E‐01 5.8E‐04 6.9E‐04 72 1057 77% 5.2E‐02 1.3E‐06 1.3E‐06

miR‐340‐5p 1.0E+00 5.8E‐04 6.9E‐04 70 1424 74% 9.4E‐02 1.3E‐06 1.3E‐06

miR‐448 8.6E‐01 2.3E‐03 6.9E‐04 68 699 71% 2.7E‐02 1.9E‐05 1.3E‐06

miR‐96‐5p/1271‐5p 7.5E‐02 3.1E‐01 6.9E‐04 64 1049 75% 7.9E‐04 3.8E‐03 1.3E‐06

miR‐376c‐3p 8.0E‐01 5.2E‐03 6.9E‐04 64 254 72% 2.1E‐02 4.5E‐05 1.3E‐06

miR‐27ab‐3p 9.8E‐01 1.9E‐03 6.9E‐04 61 1212 74% 6.8E‐02 1.6E‐05 1.3E‐06

miR‐148ab‐3p/152‐3p 5.3E‐01 3.2E‐02 6.9E‐04 60 697 77% 9.0E‐03 3.1E‐04 1.3E‐06

miR‐410‐3p 7.6E‐01 9.4E‐03 6.9E‐04 60 636 76% 1.9E‐02 8.4E‐05 1.3E‐06

miR‐485‐5p 3.4E‐01 9.1E‐02 6.9E‐04 58 379 73% 4.8E‐03 9.0E‐04 1.3E‐06

miR‐22‐3p 3.2E‐02 7.1E‐01 6.9E‐04 50 507 71% 3.2E‐04 1.5E‐02 1.3E‐06

miR‐124‐3p/506‐3p 7.8E‐01 2.4E‐02 6.9E‐04 49 1654 77% 2.0E‐02 2.2E‐04 1.3E‐06

miR‐155‐5p 5.1E‐01 7.9E‐02 7.3E‐04 49 439 76% 8.5E‐03 7.8E‐04 2.5E‐06

miR‐300/381‐3p 1.0E+00 7.9E‐03 6.9E‐04 49 881 78% 9.9E‐02 7.0E‐05 1.3E‐06

miR‐377‐3p 4.0E‐01 8.4E‐02 2.6E‐03 46 573 75% 5.9E‐03 8.2E‐04 2.1E‐05

miR‐153‐3p 9.9E‐01 1.1E‐02 6.9E‐04 46 748 72% 8.7E‐02 9.5E‐05 1.3E‐06

miR‐539‐5p 4.8E‐01 1.2E‐01 6.9E‐04 44 698 73% 7.5E‐03 1.3E‐03 1.3E‐06

miR‐26ab‐5p/1297/4465 4.9E‐01 1.3E‐01 6.9E‐04 44 884 73% 7.8E‐03 1.3E‐03 1.3E‐06

miR‐186‐5p 1.0E+00 1.6E‐02 6.9E‐04 43 859 71% 3.0E‐01 1.4E‐04 1.3E‐06

miR‐125ab‐5p/4319 9.9E‐01 3.1E‐02 6.9E‐04 38 847 75% 7.5E‐02 2.9E‐04 1.3E‐06

miR‐495‐3p 6.7E‐01 1.2E‐01 6.9E‐04 36 903 75% 1.4E‐02 1.2E‐03 1.3E‐06

miR‐384 8.7E‐01 1.7E‐02 6.2E‐03 35 302 78% 2.9E‐02 1.5E‐04 5.4E‐05

miR‐31‐5p 1.0E+00 1.5E‐02 4.1E‐03 34 368 71% 1.3E‐01 1.3E‐04 3.5E‐05

miR‐320abcd/4429 9.9E‐01 4.9E‐02 6.9E‐04 34 788 76% 7.1E‐02 4.6E‐04 1.3E‐06

miR‐181abcd‐5p/4262 3.2E‐01 4.1E‐01 6.9E‐04 33 1195 75% 4.3E‐03 5.6E‐03 1.3E‐06

miR‐223‐3p 1.0E+00 7.4E‐03 1.4E‐02 31 311 76% 3.3E‐01 6.5E‐05 1.3E‐04

miR‐150‐5p 7.2E‐01 1.5E‐01 8.3E‐04 31 282 73% 1.7E‐02 1.6E‐03 3.8E‐06

miR‐590‐3p 1.0E+00 7.3E‐02 6.9E‐04 30 1250 72% 1.8E‐01 7.1E‐04 1.3E‐06

miR‐1/206/613 7.1E‐01 1.9E‐01 6.9E‐04 30 787 76% 1.6E‐02 2.0E‐03 1.3E‐06

miR‐23ab‐3p/23c 1.0E+00 7.7E‐02 6.9E‐04 30 1125 72% 1.2E‐01 7.6E‐04 1.3E‐06

miR‐142‐3p 9.3E‐01 6.0E‐02 2.2E‐03 29 331 75% 3.8E‐02 5.8E‐04 1.8E‐05

miR‐326/330‐5p 8.8E‐01 1.2E‐01 8.3E‐04 28 444 75% 3.0E‐02 1.2E‐03 3.8E‐06

miR‐544a 1.0E+00 9.4E‐02 6.9E‐04 28 573 72% 1.7E‐01 9.3E‐04 1.3E‐06

miR‐425‐5p 3.3E‐01 3.4E‐02 1.5E‐01 27 211 75% 4.4E‐03 3.1E‐04 1.5E‐03

miR‐15ab‐5p/16‐5p/195‐5p/424‐5p/497‐5p 1.0E+00 1.1E‐01 6.9E‐04 27 1275 74% 3.2E‐01 1.1E‐03 1.3E‐06

miR‐135ab‐5p 7.4E‐01 2.3E‐01 6.9E‐04 27 716 75% 1.7E‐02 2.6E‐03 1.3E‐06


28



p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

miR‐371a‐5p 9.9E‐01 8.2E‐02 1.6E‐03 26 354 73% 9.1E‐02 8.1E‐04 1.1E‐05

miR‐342‐3p 1.0E+00 1.4E‐01 6.9E‐04 25 284 76% 1.7E‐01 1.4E‐03 1.3E‐06


miR‐205‐5p 1.0E+00 2.0E‐01 6.9E‐04 22 417 76% 5.6E‐01 2.2E‐03 1.3E‐06

miR‐133a‐3p/133b 9.3E‐01 2.5E‐01 6.9E‐04 21 648 75% 3.9E‐02 2.8E‐03 1.3E‐06

miR‐17‐5p/20ab‐5p/93‐5p/106ab‐5p/ 519d‐3p

1.0E+00 2.4E‐01 6.9E‐04 20 1220 77% 2.7E‐01 2.7E‐03 1.3E‐06

miR‐199ab‐5p 9.3E‐01 3.1E‐01 1.1E‐03 18 494 77% 4.0E‐02 3.8E‐03 7.5E‐06

miR‐370‐3p 1.0E+00 3.3E‐01 7.3E‐04 17 391 76% 2.8E‐01 4.1E‐03 2.5E‐06


9.8E‐01 3.9E‐01 6.9E‐04 16 844 74% 6.8E‐02 5.3E‐03 1.3E‐06

miR‐139‐5p 8.2E‐01 2.8E‐01 8.0E‐03 16 349 77% 2.3E‐02 3.3E‐03 7.0E‐05

miR‐144‐3p 6.1E‐01 7.5E‐01 6.9E‐04 16 878 76% 1.1E‐02 1.8E‐02 1.3E‐06

miR‐494‐3p 9.9E‐01 3.8E‐01 9.2E‐04 16 574 74% 8.8E‐02 5.1E‐03 5.0E‐06

miR‐224‐5p 8.6E‐01 5.7E‐01 6.9E‐04 15 383 75% 2.8E‐02 9.7E‐03 1.3E‐06

miR‐504‐5p/4725‐5p 1.0E+00 4.7E‐01 8.3E‐04 14 212 74% 3.2E‐01 6.8E‐03 3.8E‐06

miR‐874‐3p 1.0E+00 5.0E‐01 8.3E‐04 14 269 76% 1.7E‐01 7.6E‐03 3.8E‐06

miR‐194‐5p 9.7E‐01 3.0E‐03 4.4E‐01 13 367 80% 5.8E‐02 2.5E‐05 6.4E‐03

miR‐543 9.4E‐01 6.5E‐01 6.9E‐04 13 737 75% 4.3E‐02 1.3E‐02 1.3E‐06

miR‐216a‐5p 1.0E+00 3.5E‐01 8.8E‐03 12 287 73% 3.7E‐01 4.6E‐03 7.9E‐05

miR‐197‐3p 6.3E‐01 3.4E‐01 6.9E‐02 11 219 71% 1.2E‐02 4.2E‐03 6.7E‐04

miR‐28‐5p/708‐5p/3139 3.3E‐01 8.0E‐01 4.3E‐02 11 209 80% 4.5E‐03 2.0E‐02 4.1E‐04

miR‐499a‐5p 1.0E+00 7.0E‐01 1.3E‐03 11 340 74% 9.8E‐02 1.4E‐02 8.7E‐06

miR‐421 1.0E+00 7.1E‐01 1.6E‐03 10 433 77% 3.1E‐01 1.5E‐02 1.1E‐05

miR‐505‐3p 1.0E+00 4.0E‐01 1.5E‐02 10 236 73% 5.8E‐01 5.4E‐03 1.3E‐04

miR‐338‐3p 1.0E+00 7.5E‐01 1.3E‐03 10 311 72% 1.2E‐01 1.7E‐02 8.7E‐06

miR‐202‐3p 1.0E+00 8.3E‐01 6.9E‐04 10 798 72% 2.0E‐01 2.3E‐02 1.3E‐06

miR‐503‐5p 1.0E+00 3.2E‐01 3.2E‐02 10 387 75% 1.8E‐01 3.9E‐03 3.0E‐04

miR‐214‐3p/761/3619‐5p 1.0E+00 8.6E‐01 8.3E‐04 9 678 77% 1.5E‐01 2.7E‐02 3.8E‐06

miR‐542‐3p 9.9E‐01 3.1E‐01 4.8E‐02 9 279 74% 7.5E‐02 3.7E‐03 4.6E‐04

miR‐149‐5p 1.0E+00 9.3E‐01 6.9E‐04 9 451 75% 3.9E‐01 3.9E‐02 1.3E‐06

miR‐203a 1.0E+00 9.6E‐01 6.9E‐04 9 867 74% 1.1E‐01 4.9E‐02 1.3E‐06

miR‐145‐5p 1.0E+00 9.6E‐01 6.9E‐04 9 730 74% 2.9E‐01 5.1E‐02 1.3E‐06

miR‐103a‐3p/107 1.0E+00 9.9E‐01 6.9E‐04 8 650 76% 1.7E‐01 7.7E‐02 1.3E‐06

miR‐24‐3p 9.8E‐01 1.0E+00 7.3E‐04 8 632 73% 6.8E‐02 2.1E‐01 2.5E‐06

miR‐129‐5p 1.0E+00 9.9E‐01 6.9E‐04 8 544 75% 2.9E‐01 8.3E‐02 1.3E‐06


miR‐29abc‐3p 1.0E+00 1.0E+00 6.9E‐04 8 1077 75% 7.6E‐01 2.0E‐01 1.3E‐06

miR‐873‐5p 1.0E+00 1.0E+00 6.9E‐04 8 335 70% 5.8E‐01 2.7E‐01 1.3E‐06

miR‐33ab‐5p 9.9E‐01 8.4E‐01 4.9E‐03 7 415 76% 8.3E‐02 2.4E‐02 4.2E‐05

miR‐324‐5p 1.0E+00 4.3E‐01 4.7E‐02 7 141 71% 1.9E‐01 5.9E‐03 4.5E‐04

miR‐335‐5p 3.6E‐01 9.8E‐01 8.2E‐02 7 256 74% 5.0E‐03 5.7E‐02 8.0E‐04

miR‐216b‐5p 9.7E‐01 6.8E‐02 4.2E‐01 7 290 73% 5.3E‐02 6.4E‐04 5.9E‐03

miR‐219a‐5p/4782‐3p 1.0E+00 7.0E‐01 1.5E‐02 7 391 76% 3.8E‐01 1.5E‐02 1.3E‐04

miR‐329‐3p/362‐3p 9.4E‐01 9.8E‐01 4.9E‐03 7 314 73% 4.3E‐02 5.8E‐02 4.2E‐05

miR‐146ab‐5p 1.0E+00 5.1E‐01 5.5E‐02 7 225 74% 1.4E‐01 7.9E‐03 5.2E‐04

miR‐196ab‐5p 1.0E+00 8.9E‐01 1.1E‐02 6 295 72% 2.7E‐01 3.1E‐02 9.5E‐05

miR‐653‐5p 1.0E+00 1.0E+00 5.8E‐03 6 224 71% 1.9E‐01 1.2E‐01 4.9E‐05

miR‐217 1.0E+00 1.9E‐02 8.1E‐01 6 345 77% 1.1E‐01 1.7E‐04 2.3E‐02

miR‐143‐3p/4770 8.0E‐01 1.0E+00 2.4E‐02 6 407 73% 2.1E‐02 9.3E‐02 2.2E‐04

miR‐876‐5p/3167 9.9E‐01 1.0E+00 1.5E‐02 5 268 66% 7.8E‐02 1.3E‐01 1.4E‐04

miR‐183‐5p 1.0E+00 7.1E‐01 6.5E‐02 5 386 78% 2.9E‐01 1.5E‐02 6.2E‐04

miR‐192‐5p/215‐5p 1.0E+00 6.9E‐01 7.7E‐02 5 156 66% 1.4E‐01 1.4E‐02 7.5E‐04

miR‐122‐5p 9.9E‐01 3.7E‐02 8.8E‐01 5 172 79% 8.0E‐02 3.3E‐04 3.1E‐02

miR‐221‐3p/222‐3p 1.0E+00 5.5E‐01 1.6E‐01 5 444 76% 3.1E‐01 9.0E‐03 1.7E‐03

miR‐208ab‐3p 1.0E+00 7.7E‐01 7.8E‐02 4 182 70% 2.0E‐01 1.8E‐02 7.5E‐04


29



p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

miR‐10ab‐5p 1.0E+00 9.2E‐01 4.4E‐02 4 272 74% 7.1E‐01 3.5E‐02 4.1E‐04

miR‐383‐5p 1.0E+00 1.0E+00 3.4E‐02 4 176 75% 5.6E‐01 1.1E‐01 3.2E‐04

miR‐299‐3p 1.0E+00 9.9E‐01 4.2E‐02 4 91 80% 2.0E‐01 9.1E‐02 4.0E‐04

miR‐361‐5p 1.0E+00 1.0E+00 4.7E‐02 4 240 69% 2.6E‐01 1.6E‐01 4.5E‐04

miR‐21‐5p/590‐5p 8.7E‐01 8.0E‐01 1.5E‐01 4 308 75% 3.0E‐02 2.1E‐02 1.6E‐03

miR‐185‐5p/4306/4644 1.0E+00 1.0E+00 5.4E‐02 4 320 68% 3.8E‐01 1.5E‐01 5.1E‐04

miR‐488‐3p 1.0E+00 9.1E‐01 8.1E‐02 4 384 71% 6.4E‐01 3.4E‐02 8.0E‐04

miR‐365a‐3p 5.5E‐01 8.6E‐01 3.5E‐01 4 277 78% 9.5E‐03 2.7E‐02 4.5E‐03

miR‐486‐5p 1.0E+00 1.0E+00 6.3E‐02 4 154 76% 5.4E‐01 2.0E‐01 6.2E‐04

miR‐328‐3p 1.0E+00 8.5E‐01 1.5E‐01 3 209 76% 3.4E‐01 2.5E‐02 1.6E‐03

miR‐433‐3p 1.0E+00 1.0E+00 1.3E‐01 3 321 75% 2.4E‐01 1.4E‐01 1.3E‐03

miR‐125a‐3p 9.8E‐01 1.0E+00 1.4E‐01 3 223 72% 6.3E‐02 1.4E‐01 1.5E‐03

miR‐491‐5p 1.0E+00 9.5E‐01 1.6E‐01 3 173 74% 3.1E‐01 4.4E‐02 1.7E‐03

miR‐490‐3p 1.0E+00 1.0E+00 1.6E‐01 3 192 72% 6.3E‐01 1.1E‐01 1.7E‐03

miR‐190a‐5p/190b 1.8E‐01 9.8E‐01 1.0E+00 3 185 71% 2.0E‐03 6.3E‐02 2.1E‐01

miR‐496 1.0E+00 5.1E‐01 5.8E‐01 3 128 77% 9.6E‐02 7.8E‐03 1.0E‐02

miR‐339‐5p 1.0E+00 8.8E‐01 3.3E‐01 2 185 75% 2.9E‐01 2.9E‐02 4.3E‐03

miR‐18ab‐5p/4735‐3p 1.0E+00 9.3E‐01 4.0E‐01 2 275 73% 5.4E‐01 3.7E‐02 5.4E‐03

miR‐382‐5p 1.0E+00 5.0E‐01 8.2E‐01 2 217 71% 9.4E‐02 7.5E‐03 2.3E‐02

miR‐375 1.0E+00 9.9E‐01 3.9E‐01 2 229 76% 6.5E‐01 7.7E‐02 5.4E‐03

miR‐193ab‐3p 1.0E+00 1.0E+00 4.4E‐01 2 222 79% 6.6E‐01 1.4E‐01 6.4E‐03

miR‐136‐5p 1.0E+00 9.9E‐01 4.7E‐01 2 272 67% 2.2E‐01 7.1E‐02 7.0E‐03

miR‐378a‐3p/378bcdefhi/422a 1.0E+00 1.0E+00 4.8E‐01 2 191 73% 3.0E‐01 1.7E‐01 7.4E‐03

miR‐376ab‐3p 1.0E+00 1.0E+00 4.9E‐01 2 214 75% 5.0E‐01 4.9E‐01 7.7E‐03

miR‐455‐5p 1.0E+00 1.0E+00 5.3E‐01 2 198 77% 7.8E‐01 2.8E‐01 8.7E‐03

miR‐134‐5p/3118 9.1E‐01 8.1E‐01 8.2E‐01 2 171 75% 3.6E‐02 2.1E‐02 2.4E‐02

miR‐346 1.0E+00 1.0E+00 5.7E‐01 2 143 74% 3.2E‐01 1.5E‐01 9.8E‐03

miR‐191‐5p 9.1E‐01 1.0E+00 6.5E‐01 2 54 78% 3.6E‐02 1.1E‐01 1.3E‐02

miR‐140‐5p 1.0E+00 1.0E+00 7.8E‐01 1 345 77% 3.2E‐01 3.0E‐01 2.0E‐02

miR‐758‐3p 1.0E+00 1.0E+00 8.0E‐01 1 235 70% 9.8E‐01 9.1E‐01 2.1E‐02

miR‐154‐5p 1.0E+00 1.0E+00 8.0E‐01 1 129 77% 2.0E‐01 1.0E‐01 2.2E‐02

miR‐599 1.0E+00 9.8E‐01 9.5E‐01 1 209 71% 3.5E‐01 6.5E‐02 4.8E‐02

miR‐431‐5p 1.0E+00 1.0E+00 9.4E‐01 1 167 75% 1.6E‐01 3.8E‐01 4.2E‐02

miR‐99ab‐5p/100‐5p 1.0E+00 9.9E‐01 9.6E‐01 1 56 86% 8.3E‐01 7.6E‐02 5.3E‐02

miR‐411‐5p 1.0E+00 1.0E+00 9.6E‐01 1 106 78% 6.6E‐01 5.5E‐01 5.2E‐02

miR‐875‐5p 1.0E+00 1.0E+00 9.7E‐01 1 110 81% 2.0E‐01 2.6E‐01 5.4E‐02

miR‐296‐3p 1.0E+00 1.0E+00 9.9E‐01 1 66 69% 1.8E‐01 1.4E‐01 8.3E‐02

miR‐379‐5p/3529‐5p 1.0E+00 1.0E+00 1.0E+00 1 93 66% 5.4E‐01 1.4E‐01 1.9E‐01












30


eTable 4: Alternative TargetScan gene set analysis: lower LD-threshold and longer clumping range. These are the results of the main gene set analysis (eTable 1) with the change that the clumping range was 3000 kb and the LD threshold was lowered to 0.1.


p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

miR‐218‐5p 2.0E‐03 6.7E‐04 7.6E‐04 492 931 75% 1.6E‐05 1.3E‐06 1.3E‐06

miR‐137 1.8E‐02 6.7E‐04 7.6E‐04 341 1144 77% 1.8E‐04 1.3E‐06 1.3E‐06


miR‐101‐3p 2.0E‐02 7.2E‐03 7.6E‐04 237 803 78% 2.0E‐04 6.2E‐05 1.3E‐06

miR‐182‐5p 5.9E‐02 1.8E‐03 7.6E‐04 228 1122 73% 6.1E‐04 1.4E‐05 1.3E‐06

miR‐9‐5p 5.8E‐02 3.1E‐03 7.6E‐04 213 1237 75% 5.9E‐04 2.5E‐05 1.3E‐06


miR‐204‐5p/211‐5p 1.5E‐01 1.2E‐03 7.6E‐04 185 670 76% 1.7E‐03 7.5E‐06 1.3E‐06

miR‐132‐3p/212‐3p 2.3E‐01 2.6E‐03 9.3E‐04 137 406 79% 2.8E‐03 2.0E‐05 3.8E‐06

miR‐141‐3p/200a‐3p 1.8E‐01 5.9E‐03 7.6E‐04 135 744 76% 2.1E‐03 5.2E‐05 1.3E‐06

miR‐7‐5p 6.0E‐02 3.4E‐02 1.1E‐03 130 444 73% 6.1E‐04 3.2E‐04 5.0E‐06

miR‐130ab‐3p/301a‐3p/301b/ 454‐3p/3666/4295

3.6E‐01 1.7E‐03 7.6E‐04 121 899 76% 5.1E‐03 1.3E‐05 1.3E‐06

miR‐22‐3p 1.6E‐02 2.2E‐01 7.6E‐04 106 507 71% 1.5E‐04 2.5E‐03 1.3E‐06

miR‐138‐5p 2.0E‐02 3.1E‐01 9.3E‐04 86 560 77% 1.9E‐04 3.7E‐03 3.8E‐06

miR‐19ab‐3p 3.0E‐01 3.3E‐02 7.6E‐04 79 1167 75% 4.0E‐03 3.1E‐04 1.3E‐06

miR‐374ab‐5p 8.6E‐01 8.1E‐04 9.3E‐04 75 678 71% 2.8E‐02 3.8E‐06 3.8E‐06

miR‐448 8.1E‐01 1.4E‐03 7.6E‐04 75 699 71% 2.3E‐02 1.0E‐05 1.3E‐06

miR‐539‐5p 3.6E‐01 3.3E‐02 7.6E‐04 73 698 73% 4.9E‐03 3.1E‐04 1.3E‐06

miR‐340‐5p 9.9E‐01 6.7E‐04 7.6E‐04 69 1424 74% 7.9E‐02 1.3E‐06 1.3E‐06

miR‐200bc‐3p/429 9.9E‐01 6.7E‐04 7.6E‐04 69 1057 77% 8.3E‐02 1.3E‐06 1.3E‐06

miR‐410‐3p 6.9E‐01 7.2E‐03 7.6E‐04 67 636 76% 1.5E‐02 6.2E‐05 1.3E‐06

miR‐376c‐3p 7.0E‐01 7.0E‐03 7.6E‐04 66 254 72% 1.5E‐02 6.1E‐05 1.3E‐06

miR‐96‐5p/1271‐5p 1.4E‐01 2.7E‐01 7.6E‐04 56 1049 75% 1.6E‐03 3.1E‐03 1.3E‐06

miR‐27ab‐3p 1.0E+00 4.7E‐03 7.6E‐04 52 1212 74% 1.4E‐01 4.1E‐05 1.3E‐06

miR‐128‐3p 8.0E‐01 1.6E‐02 7.6E‐04 52 1047 75% 2.2E‐02 1.4E‐04 1.3E‐06

miR‐142‐3p 6.9E‐01 2.8E‐02 9.3E‐04 50 331 75% 1.5E‐02 2.5E‐04 3.8E‐06

miR‐300/381‐3p 1.0E+00 6.7E‐03 7.6E‐04 49 881 78% 1.7E‐01 5.9E‐05 1.3E‐06

miR‐186‐5p 1.0E+00 7.9E‐03 8.5E‐04 47 859 71% 1.6E‐01 6.7E‐05 2.5E‐06

miR‐125ab‐5p/4319 1.0E+00 1.1E‐02 7.6E‐04 45 847 75% 1.7E‐01 1.0E‐04 1.3E‐06

miR‐150‐5p 6.1E‐01 5.2E‐02 1.5E‐03 44 282 73% 1.2E‐02 5.0E‐04 8.7E‐06

miR‐148ab‐3p/152‐3p 4.9E‐01 1.2E‐01 8.5E‐04 43 697 77% 8.0E‐03 1.2E‐03 2.5E‐06

miR‐153‐3p 1.0E+00 1.4E‐02 7.6E‐04 43 748 72% 1.7E‐01 1.2E‐04 1.3E‐06

miR‐124‐3p/506‐3p 7.4E‐01 4.8E‐02 7.6E‐04 43 1654 77% 1.7E‐02 4.5E‐04 1.3E‐06

miR‐377‐3p 4.1E‐01 1.8E‐01 1.1E‐03 40 573 75% 6.0E‐03 1.9E‐03 5.0E‐06

miR‐320abcd/4429 9.3E‐01 3.3E‐02 7.6E‐04 39 788 76% 4.1E‐02 3.1E‐04 1.3E‐06

miR‐31‐5p 1.0E+00 1.1E‐02 2.9E‐03 38 368 71% 1.2E‐01 9.4E‐05 2.3E‐05

miR‐223‐3p 1.0E+00 8.6E‐03 4.0E‐03 38 311 76% 2.6E‐01 7.6E‐05 3.3E‐05

miR‐181abcd‐5p/4262 3.2E‐01 3.3E‐01 7.6E‐04 37 1195 75% 4.5E‐03 4.1E‐03 1.3E‐06

miR‐155‐5p 7.9E‐01 6.8E‐02 8.5E‐04 37 439 76% 2.1E‐02 6.4E‐04 2.5E‐06

miR‐485‐5p 4.8E‐01 2.1E‐01 7.6E‐04 37 379 73% 7.6E‐03 2.3E‐03 1.3E‐06

miR‐342‐3p 1.0E+00 3.4E‐02 7.6E‐04 36 284 76% 2.1E‐01 3.2E‐04 1.3E‐06

miR‐326/330‐5p 9.2E‐01 5.5E‐02 9.3E‐04 34 444 75% 3.7E‐02 5.3E‐04 3.8E‐06

miR‐495‐3p 8.7E‐01 8.3E‐02 7.6E‐04 33 903 75% 2.9E‐02 8.0E‐04 1.3E‐06

miR‐384 9.2E‐01 3.7E‐02 2.6E‐03 32 302 78% 3.9E‐02 3.4E‐04 2.0E‐05


miR‐135ab‐5p 8.7E‐01 1.1E‐01 7.6E‐04 30 716 75% 2.9E‐02 1.1E‐03 1.3E‐06

miR‐590‐3p 1.0E+00 7.9E‐02 7.6E‐04 29 1250 72% 1.9E‐01 7.6E‐04 1.3E‐06

miR‐26ab‐5p/1297/4465 6.3E‐01 2.7E‐01 7.6E‐04 28 884 73% 1.2E‐02 3.3E‐03 1.3E‐06

miR‐544a 1.0E+00 9.4E‐02 7.6E‐04 28 573 72% 2.1E‐01 9.4E‐04 1.3E‐06

miR‐371a‐5p 1.0E+00 6.1E‐02 2.0E‐03 27 354 73% 1.8E‐01 5.8E‐04 1.4E‐05


31



p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

miR‐133a‐3p/133b 8.7E‐01 1.9E‐01 7.6E‐04 25 648 75% 2.9E‐02 2.1E‐03 1.3E‐06

miR‐503‐5p 1.0E+00 5.8E‐02 4.7E‐03 24 387 75% 2.6E‐01 5.6E‐04 3.9E‐05

miR‐23ab‐3p/23c 9.9E‐01 1.4E‐01 7.6E‐04 24 1125 72% 7.5E‐02 1.5E‐03 1.3E‐06

miR‐1/206/613 9.2E‐01 2.1E‐01 7.6E‐04 23 787 76% 3.7E‐02 2.4E‐03 1.3E‐06

miR‐494‐3p 1.0E+00 2.0E‐01 8.5E‐04 21 574 74% 1.4E‐01 2.1E‐03 2.5E‐06

miR‐224‐5p 8.7E‐01 2.7E‐01 9.3E‐04 21 383 75% 2.9E‐02 3.3E‐03 3.8E‐06

miR‐15ab‐5p/16‐5p/195‐5p/424‐5p/497‐5p 1.0E+00 2.3E‐01 7.6E‐04 20 1275 74% 3.6E‐01 2.6E‐03 1.3E‐06

miR‐197‐3p 6.5E‐01 8.0E‐02 4.8E‐02 20 219 71% 1.3E‐02 7.8E‐04 4.5E‐04

miR‐425‐5p 3.3E‐01 7.5E‐02 2.0E‐01 20 211 75% 4.6E‐03 7.2E‐04 2.2E‐03

miR‐17‐5p/20ab‐5p/93‐5p/106ab‐5p/ 519d‐3p

1.0E+00 2.5E‐01 7.6E‐04 19 1220 77% 3.2E‐01 2.9E‐03 1.3E‐06

miR‐144‐3p 5.8E‐01 6.3E‐01 7.6E‐04 19 878 76% 1.1E‐02 1.2E‐02 1.3E‐06

miR‐219a‐5p/4782‐3p 1.0E+00 2.7E‐01 9.3E‐04 18 391 76% 4.1E‐01 3.3E‐03 3.8E‐06

miR‐199ab‐5p 9.6E‐01 3.2E‐01 1.1E‐03 17 494 77% 5.2E‐02 4.0E‐03 5.0E‐06

miR‐33ab‐5p 9.8E‐01 3.1E‐01 1.1E‐03 17 415 76% 7.0E‐02 3.8E‐03 5.0E‐06

miR‐370‐3p 1.0E+00 3.4E‐01 7.6E‐04 17 391 76% 2.8E‐01 4.3E‐03 1.3E‐06

miR‐505‐3p 1.0E+00 1.7E‐01 6.9E‐03 17 236 73% 5.5E‐01 1.8E‐03 6.0E‐05

miR‐216b‐5p 9.4E‐01 1.7E‐02 1.2E‐01 16 290 73% 4.5E‐02 1.6E‐04 1.3E‐03

miR‐194‐5p 8.9E‐01 3.1E‐03 3.7E‐01 15 367 80% 3.2E‐02 2.5E‐05 5.1E‐03

miR‐543 7.7E‐01 6.8E‐01 7.6E‐04 14 737 75% 2.0E‐02 1.4E‐02 1.3E‐06


1.0E+00 4.9E‐01 7.6E‐04 14 844 74% 1.5E‐01 7.4E‐03 1.3E‐06

miR‐205‐5p 1.0E+00 5.4E‐01 8.5E‐04 13 417 76% 6.2E‐01 8.8E‐03 2.5E‐06

miR‐874‐3p 1.0E+00 5.8E‐01 7.6E‐04 13 269 76% 2.3E‐01 9.9E‐03 1.3E‐06

miR‐139‐5p 8.7E‐01 4.7E‐01 5.0E‐03 13 349 77% 2.9E‐02 7.0E‐03 4.2E‐05

miR‐499a‐5p 8.9E‐01 7.3E‐01 7.6E‐04 12 340 74% 3.2E‐02 1.6E‐02 1.3E‐06

miR‐28‐5p/708‐5p/3139 5.3E‐01 5.1E‐01 3.8E‐02 12 209 80% 9.0E‐03 7.9E‐03 3.6E‐04

miR‐504‐5p/4725‐5p 1.0E+00 5.7E‐01 1.8E‐03 11 212 74% 4.4E‐01 9.7E‐03 1.1E‐05

miR‐145‐5p 1.0E+00 6.8E‐01 7.6E‐04 11 730 74% 3.4E‐01 1.4E‐02 1.3E‐06

miR‐338‐3p 9.9E‐01 6.5E‐01 1.2E‐03 11 311 72% 7.8E‐02 1.3E‐02 6.2E‐06

miR‐324‐5p 1.0E+00 1.7E‐01 7.3E‐02 10 141 71% 3.6E‐01 1.8E‐03 7.1E‐04

miR‐365a‐3p 4.0E‐01 8.0E‐01 4.6E‐02 10 277 78% 5.6E‐03 2.1E‐02 4.3E‐04

miR‐221‐3p/222‐3p 1.0E+00 5.1E‐01 8.9E‐03 10 444 76% 3.0E‐01 7.9E‐03 7.7E‐05

miR‐202‐3p 1.0E+00 8.6E‐01 7.6E‐04 9 798 72% 1.4E‐01 2.6E‐02 1.3E‐06

miR‐216a‐5p 1.0E+00 4.4E‐01 1.6E‐02 9 287 73% 4.7E‐01 6.4E‐03 1.4E‐04

miR‐335‐5p 3.4E‐01 8.3E‐01 6.7E‐02 9 256 74% 4.7E‐03 2.3E‐02 6.6E‐04

miR‐183‐5p 9.9E‐01 2.1E‐01 8.8E‐02 9 386 78% 9.0E‐02 2.3E‐03 8.6E‐04

miR‐203a 9.9E‐01 9.6E‐01 7.6E‐04 9 867 74% 7.9E‐02 5.0E‐02 1.3E‐06

miR‐192‐5p/215‐5p 9.8E‐01 4.2E‐01 3.2E‐02 9 156 66% 6.3E‐02 5.8E‐03 2.9E‐04

miR‐129‐5p 1.0E+00 9.8E‐01 7.6E‐04 8 544 75% 1.7E‐01 6.0E‐02 1.3E‐06

miR‐103a‐3p/107 1.0E+00 9.9E‐01 7.6E‐04 8 650 76% 2.8E‐01 8.1E‐02 1.3E‐06

miR‐149‐5p 1.0E+00 9.9E‐01 7.6E‐04 8 451 75% 3.8E‐01 9.1E‐02 1.3E‐06


miR‐29abc‐3p 1.0E+00 1.0E+00 7.6E‐04 8 1077 75% 7.8E‐01 2.8E‐01 1.3E‐06

miR‐24‐3p 1.0E+00 1.0E+00 8.5E‐04 8 632 73% 1.1E‐01 3.3E‐01 2.5E‐06

miR‐214‐3p/761/3619‐5p 1.0E+00 9.9E‐01 1.4E‐03 8 678 77% 1.7E‐01 7.8E‐02 7.5E‐06

miR‐329‐3p/362‐3p 8.1E‐01 9.5E‐01 7.0E‐03 8 314 73% 2.2E‐02 4.6E‐02 6.1E‐05

miR‐873‐5p 1.0E+00 1.0E+00 2.0E‐03 7 335 70% 5.1E‐01 3.5E‐01 1.4E‐05

miR‐146ab‐5p 1.0E+00 4.5E‐01 4.9E‐02 7 225 74% 1.9E‐01 6.5E‐03 4.6E‐04

miR‐208ab‐3p 1.0E+00 6.5E‐01 3.2E‐02 6 182 70% 1.1E‐01 1.3E‐02 3.0E‐04

miR‐653‐5p 1.0E+00 9.9E‐01 5.8E‐03 6 224 71% 2.4E‐01 8.0E‐02 5.0E‐05

miR‐542‐3p 9.8E‐01 4.6E‐01 9.3E‐02 6 279 74% 6.2E‐02 6.7E‐03 9.3E‐04

miR‐122‐5p 9.7E‐01 6.4E‐02 5.6E‐01 6 172 79% 6.0E‐02 5.9E‐04 9.8E‐03

miR‐421 1.0E+00 7.7E‐01 2.7E‐02 6 433 77% 2.6E‐01 1.8E‐02 2.4E‐04

miR‐361‐5p 1.0E+00 1.0E+00 1.0E‐02 6 240 69% 3.4E‐01 1.4E‐01 8.9E‐05

miR‐488‐3p 1.0E+00 7.6E‐01 4.7E‐02 5 384 71% 5.9E‐01 1.8E‐02 4.5E‐04


32



p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

miR‐10ab‐5p 1.0E+00 8.9E‐01 2.8E‐02 5 272 74% 8.5E‐01 3.1E‐02 2.6E‐04

miR‐125a‐3p 9.9E‐01 9.2E‐01 2.7E‐02 5 223 72% 7.8E‐02 3.7E‐02 2.4E‐04

miR‐217 1.0E+00 4.1E‐02 8.2E‐01 5 345 77% 1.9E‐01 3.8E‐04 2.4E‐02

miR‐21‐5p/590‐5p 9.5E‐01 7.7E‐01 8.1E‐02 5 308 75% 4.8E‐02 1.9E‐02 7.8E‐04

miR‐383‐5p 1.0E+00 9.9E‐01 2.8E‐02 5 176 75% 4.7E‐01 8.1E‐02 2.6E‐04

miR‐185‐5p/4306/4644 1.0E+00 1.0E+00 3.2E‐02 4 320 68% 4.1E‐01 2.1E‐01 2.9E‐04

miR‐491‐5p 1.0E+00 9.5E‐01 4.3E‐02 4 173 74% 4.0E‐01 4.6E‐02 4.0E‐04

miR‐876‐5p/3167 9.7E‐01 9.9E‐01 4.3E‐02 4 268 66% 5.7E‐02 9.2E‐02 4.0E‐04

miR‐433‐3p 1.0E+00 1.0E+00 3.9E‐02 4 321 75% 3.3E‐01 1.1E‐01 3.7E‐04

miR‐143‐3p/4770 9.6E‐01 9.5E‐01 5.6E‐02 4 407 73% 4.9E‐02 4.7E‐02 5.4E‐04

miR‐299‐3p 1.0E+00 9.8E‐01 4.7E‐02 4 91 80% 2.9E‐01 6.5E‐02 4.5E‐04

miR‐196ab‐5p 1.0E+00 9.1E‐01 6.3E‐02 4 295 72% 3.0E‐01 3.5E‐02 5.9E‐04

miR‐486‐5p 1.0E+00 1.0E+00 6.1E‐02 4 154 76% 2.3E‐01 1.7E‐01 5.8E‐04

miR‐328‐3p 1.0E+00 5.2E‐01 4.5E‐01 3 209 76% 3.5E‐01 8.2E‐03 6.8E‐03

miR‐193ab‐3p 1.0E+00 9.8E‐01 1.6E‐01 3 222 79% 7.0E‐01 6.2E‐02 1.7E‐03

miR‐382‐5p 1.0E+00 5.0E‐01 5.0E‐01 3 217 71% 1.0E‐01 7.7E‐03 8.0E‐03

miR‐190a‐5p/190b 2.5E‐01 8.6E‐01 1.0E+00 3 185 71% 3.1E‐03 2.6E‐02 1.0E‐01

miR‐455‐5p 1.0E+00 1.0E+00 1.8E‐01 3 198 77% 6.3E‐01 1.5E‐01 2.0E‐03

miR‐378a‐3p/378bcdefhi/422a 1.0E+00 1.0E+00 2.2E‐01 3 191 73% 2.6E‐01 1.7E‐01 2.5E‐03

miR‐154‐5p 9.9E‐01 1.0E+00 2.7E‐01 2 129 77% 9.7E‐02 9.5E‐02 3.3E‐03

miR‐140‐5p 1.0E+00 1.0E+00 2.8E‐01 2 345 77% 3.0E‐01 2.1E‐01 3.5E‐03

miR‐339‐5p 1.0E+00 9.2E‐01 4.1E‐01 2 185 75% 2.9E‐01 3.6E‐02 5.8E‐03

miR‐490‐3p 1.0E+00 9.6E‐01 3.8E‐01 2 192 72% 5.3E‐01 4.9E‐02 5.3E‐03

miR‐496 1.0E+00 7.2E‐01 6.6E‐01 2 128 77% 1.3E‐01 1.5E‐02 1.3E‐02

miR‐18ab‐5p/4735‐3p 1.0E+00 9.2E‐01 5.1E‐01 2 275 73% 5.1E‐01 3.6E‐02 8.2E‐03

miR‐376ab‐3p 1.0E+00 1.0E+00 4.7E‐01 2 214 75% 4.0E‐01 4.4E‐01 7.2E‐03

miR‐191‐5p 9.8E‐01 1.0E+00 5.7E‐01 2 54 78% 6.6E‐02 1.1E‐01 9.9E‐03

miR‐134‐5p/3118 9.8E‐01 9.7E‐01 6.9E‐01 1 171 75% 6.1E‐02 5.6E‐02 1.5E‐02

miR‐136‐5p 1.0E+00 9.1E‐01 7.5E‐01 1 272 67% 2.0E‐01 3.5E‐02 1.8E‐02

miR‐346 1.0E+00 9.8E‐01 8.1E‐01 1 143 74% 3.5E‐01 6.6E‐02 2.3E‐02

miR‐875‐5p 1.0E+00 1.0E+00 7.9E‐01 1 110 81% 2.2E‐01 2.7E‐01 2.1E‐02

miR‐375 1.0E+00 1.0E+00 8.5E‐01 1 229 76% 4.2E‐01 1.6E‐01 2.6E‐02

miR‐431‐5p 1.0E+00 1.0E+00 8.5E‐01 1 167 75% 1.7E‐01 3.9E‐01 2.7E‐02

miR‐296‐3p 1.0E+00 1.0E+00 8.6E‐01 1 66 69% 2.9E‐01 9.3E‐02 2.9E‐02

miR‐758‐3p 1.0E+00 1.0E+00 8.8E‐01 1 235 70% 9.6E‐01 8.1E‐01 3.1E‐02

miR‐599 1.0E+00 9.9E‐01 9.1E‐01 1 209 71% 4.7E‐01 7.7E‐02 3.8E‐02

miR‐99ab‐5p/100‐5p 1.0E+00 9.8E‐01 9.8E‐01 1 56 86% 9.0E‐01 6.0E‐02 6.7E‐02

miR‐411‐5p 1.0E+00 1.0E+00 9.8E‐01 1 106 78% 3.2E‐01 4.2E‐01 6.9E‐02

miR‐379‐5p/3529‐5p 1.0E+00 1.0E+00 1.0E+00 1 93 66% 5.7E‐01 2.1E‐01 2.1E‐01












33


eTable 5: Validation of top-10 gene sets using MiRanda target predictions. Of the two groups of predictions in MiRanda, only the group “Good mirSVR score” was used. In order to match these algorithms to the TargetScan miRNA families, the union of predictions for the individual miRNA members in the TargetScan family was taken. The three different thresholds represent the different significance thresholds for the index-SNP used in clumping. Top-1% of SNPs have p-values less than 3.420 x 10-4, top 5% of SNPs have p-values less than 1.096 x 10-2. “OSF = Original set found” indicates the fraction of the TargetScan predictions also predicted by MiRanda. ”Corrected” are the p-values after correcting for multiple testing, whereas “Raw” are the unadjusted p-values. For a detailed description of the “Score” column please refer to the main text. MiRanda top‐10 validation (R2=0.6, 500kb)

p‐value @1E‐5


p‐value @top5%

Score

Size

OSF

p‐value @1E‐5


p‐value @top5%

miR‐9‐5p 1.5E‐01 5.0E‐02 1.3E‐04 116 3294 67% 2.0E‐02 6.0E‐03 1.3E‐06

miR‐200bc‐3p/429 3.6E‐01 2.9E‐02 1.3E‐04 91 4312 84% 5.6E‐02 3.4E‐03 1.3E‐06

miR‐7‐5p 1.1E‐01 2.1E‐01 1.3E‐04 82 2964 74% 1.4E‐02 2.9E‐02 1.3E‐06

miR‐101‐3p 7.9E‐01 1.1E‐01 1.4E‐04 39 3170 76% 1.9E‐01 1.4E‐02 3.8E‐06

miR‐485‐5p 6.8E‐01 4.2E‐01 1.3E‐04 26 3285 64% 1.4E‐01 6.8E‐02 1.3E‐06


miR‐1/206/613 6.5E‐01 4.6E‐01 6.8E‐04 21 3237 73% 1.4E‐01 7.8E‐02 6.0E‐05

miR‐137 9.4E‐01 8.3E‐01 1.8E‐04 12 3050 71% 3.5E‐01 2.3E‐01 6.2E‐06

miR‐374ab‐5p 9.5E‐01 9.9E‐01 1.3E‐04 11 5253 90% 3.8E‐01 5.7E‐01 1.3E‐06

miR‐28‐5p/708‐5p/3139 9.9E‐01 1.0E+00 1.3E‐04 10 2794 64% 5.6E‐01 7.7E‐01 1.3E‐06


34


eTable 6: Validation of top-10 gene sets using TargetMiner target predictions. In order to match these algorithms to the TargetScan miRNA families, the union of predictions for the individual miRNA members in the TargetScan family was taken. The three different thresholds represent the different significance thresholds for the index-SNP used in clumping. Top-1% of SNPs have p-values less than 3.420 x 10-4, top 5% of SNPs have p-values less than 1.096 x 10-2. “OSF = Original set found” indicates the fraction of the TargetScan predictions also predicted by MiRanda. ”Corrected” are the p-values after correcting for multiple testing, whereas “Raw” are the unadjusted p-values. For a detailed description of the “Score” column please refer to the main text. TargetMiner top‐10 validation (R2=0.6, 500kb)

p‐value @1E‐5


p‐value @top5%

Score

Size

OSF

p‐value @1E‐5


p‐value @top5%

miR‐7‐5p 1.7E‐02 3.1E‐04 6.8E‐04 380 4385 62% 2.4E‐03 2.8E‐05 7.5E‐05


miR‐28‐5p/708‐5p/3139 1.8E‐01 1.3E‐02 2.8E‐02 67 3571 57% 2.9E‐02 1.6E‐03 3.5E‐03

miR‐485‐5p 1.7E‐01 5.2E‐02 1.1E‐01 34 1206 40% 2.9E‐02 6.9E‐03 1.7E‐02

miR‐9‐5p 7.8E‐01 2.7E‐03 7.0E‐01 12 1255 30% 2.5E‐01 3.2E‐04 2.0E‐01

miR‐137 6.0E‐01 1.7E‐02 9.2E‐01 8 713 23% 1.5E‐01 2.1E‐03 4.2E‐01

miR‐1/206/613 6.3E‐01 4.9E‐02 7.6E‐01 7 1001 35% 1.6E‐01 6.5E‐03 2.4E‐01

miR‐101‐3p 9.7E‐01 1.5E‐01 3.6E‐01 6 1984 48% 5.4E‐01 2.4E‐02 7.0E‐02

miR‐374ab‐5p 7.0E‐01 1.3E‐01 9.8E‐01 4 600 23% 2.0E‐01 1.8E‐02 6.1E‐01

miR‐200bc‐3p/429 9.5E‐01 2.2E‐01 9.8E‐01 3 274 12% 4.9E‐01 3.6E‐02 5.8E‐01


35


eTable 7: Results for the top-10 gene sets filtered with CLIP-data from 58 ex-periments. miRNA target sites were defined to be supported by CLIP data if the seed-region of the target sites were completely within a CLIP peak. The three different thresholds represent the different significance thresholds for the index-SNP used in clumping. Top-1% of SNPs have p-values less than 3.420 x 10-4, top 5% of SNPs have p-values less than 1.096 x 10-2. “OSF = Original set found” indicates the fraction of the TargetScan predictions also predicted by MiRanda. ”Corrected” are the p-values after correcting for multiple testing, whereas “Raw” are the unadjusted p-values. For a detailed description of the “Score” column please refer to the main text. TargetScan top‐10 CLIP‐filtered (R2=0.6, 500kb)

p‐value @1E‐5


p‐value @top5%

Score

Size

OSF

p‐value @1E‐5


p‐value @top5%

miR‐485‐5p 2.9E‐01 4.5E‐02 2.7E‐03 63 120 32% 4.2E‐02 5.7E‐03 3.0E‐04

miR‐7‐5p 3.2E‐01 1.0E‐02 2.9E‐02 54 256 57% 4.8E‐02 1.3E‐03 3.4E‐03

miR‐9‐5p 8.4E‐02 4.9E‐02 7.1E‐02 51 539 44% 1.1E‐02 6.1E‐03 8.8E‐03

miR‐101‐3p 5.2E‐01 3.0E‐02 5.3E‐02 29 585 74% 9.2E‐02 3.7E‐03 6.7E‐03

miR‐1/206/613 6.4E‐01 2.9E‐01 1.5E‐02 17 411 52% 1.4E‐01 4.2E‐02 1.7E‐03


miR‐28‐5p/708‐5p/3139 2.5E‐01 1.9E‐01 3.2E‐01 14 93 46% 4.0E‐02 2.6E‐02 4.5E‐02

miR‐137 9.1E‐01 5.3E‐02 2.8E‐01 10 606 54% 3.0E‐01 6.9E‐03 4.1E‐02

miR‐200bc‐3p/429 9.8E‐01 1.4E‐01 5.7E‐01 5 572 55% 4.6E‐01 1.8E‐02 1.0E‐01

miR‐374ab‐5p 9.9E‐01 4.2E‐01 6.3E‐01 3 402 60% 4.8E‐01 6.7E‐02 1.2E‐01


36


eTable 8: Signal for the top-10 gene sets in three unrelated traits. The top 10 conserved miRNA gene sets (Table 1), were tested in three well powered alternative GWAS traits10-12 to assess if the signal was specific or a general finding common to many traits. The three different thresholds represent the different significance thresholds for the index-SNP used in clumping. “Size” indicates the number of genes in the gene set. “Size” indicates the number of genes in the gene set. “Brain” indicates the percentage of the test genes expressed in the brain. ”Corrected” are the p-values after correcting for multiple testing, whereas “Raw” are the unadjusted p-values. For a detailed description of the “Score” column please refer to the main text.

Signal in other traits (R2=0.6, 500kb)

p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

Age at menarche

miR‐485‐5p 2.1E‐01 9.5E‐01 9.1E‐01 3 379 73% 3.3E‐02 3.4E‐01 2.9E‐01

miR‐101‐3p 5.7E‐01 7.0E‐01 1.0E+00 2 803 78% 1.2E‐01 1.5E‐01 1.0E+00

miR‐200bc‐3p/429 5.6E‐01 9.5E‐01 1.0E+00 2 1057 77% 1.1E‐01 3.4E‐01 9.9E‐01

miR‐1/206/613 5.4E‐01 1.0E+00 1.0E+00 2 787 76% 1.0E‐01 6.3E‐01 9.7E‐01

miR‐374ab‐5p 1.0E+00 6.3E‐01 1.0E+00 1 678 71% 9.1E‐01 1.3E‐01 9.5E‐01

miR‐9‐5p 7.2E‐01 9.1E‐01 1.0E+00 1 1237 75% 1.7E‐01 2.9E‐01 1.0E+00

miR‐34ac‐5p/449b‐5p/449a 6.6E‐01 1.0E+00 1.0E+00 1 655 78% 1.5E‐01 7.8E‐01 1.0E+00

miR‐7‐5p 8.6E‐01 1.0E+00 1.0E+00 1 444 73% 2.5E‐01 6.1E‐01 6.4E‐01

miR‐28‐5p/708‐5p/3139 9.4E‐01 9.7E‐01 1.0E+00 1 209 80% 3.4E‐01 4.0E‐01 7.4E‐01

miR‐137 9.9E‐01 1.0E+00 1.0E+00 1 1144 77% 5.4E‐01 8.7E‐01 1.0E+00

Crohn’s disease

miR‐28‐5p/708‐5p/3139 8.3E‐01 7.8E‐01 1.0E+00 1 209 80% 2.4E‐01 1.8E‐01 8.0E‐01

miR‐137 8.5E‐01 1.0E+00 1.0E+00 1 1144 77% 2.5E‐01 7.4E‐01 1.0E+00

miR‐101‐3p 9.5E‐01 9.8E‐01 1.0E+00 1 803 78% 3.8E‐01 4.2E‐01 1.0E+00

miR‐1/206/613 1.0E+00 1.0E+00 9.8E‐01 1 787 76% 7.0E‐01 9.1E‐01 4.2E‐01

miR‐7‐5p 1.0E+00 1.0E+00 1.0E+00 1 444 73% 6.2E‐01 5.9E‐01 8.9E‐01

miR‐485‐5p 1.0E+00 1.0E+00 1.0E+00 1 379 73% 5.9E‐01 6.9E‐01 8.7E‐01

miR‐374ab‐5p 1.0E+00 1.0E+00 1.0E+00 1 678 71% 9.0E‐01 6.4E‐01 9.8E‐01

miR‐9‐5p 1.0E+00 1.0E+00 1.0E+00 1 1237 75% 8.2E‐01 6.9E‐01 9.9E‐01

miR‐34ac‐5p/449b‐5p/449a 1.0E+00 1.0E+00 1.0E+00 1 655 78% 7.9E‐01 7.5E‐01 9.8E‐01

miR‐200bc‐3p/429 1.0E+00 1.0E+00 1.0E+00 1 1057 77% 8.8E‐01 9.5E‐01 1.0E+00

Height

miR‐1/206/613 6.6E‐02 9.6E‐01 1.5E‐01 11 787 76% 7.9E‐03 3.6E‐01 1.9E‐02

miR‐485‐5p 3.4E‐01 9.2E‐01 4.6E‐01 4 379 73% 5.0E‐02 3.0E‐01 7.4E‐02

miR‐7‐5p 8.8E‐01 9.9E‐01 2.4E‐01 3 444 73% 2.6E‐01 5.1E‐01 3.2E‐02

miR‐9‐5p 9.7E‐01 4.3E‐01 9.3E‐01 2 1237 75% 3.9E‐01 7.1E‐02 3.2E‐01

miR‐200bc‐3p/429 8.5E‐01 9.7E‐01 5.6E‐01 2 1057 77% 2.3E‐01 4.0E‐01 1.0E‐01

miR‐101‐3p 6.2E‐01 9.9E‐01 9.5E‐01 2 803 78% 1.2E‐01 5.1E‐01 3.6E‐01

miR‐28‐5p/708‐5p/3139 1.0E+00 9.2E‐01 8.4E‐01 1 209 80% 7.7E‐01 3.0E‐01 2.2E‐01

miR‐34ac‐5p/449b‐5p/449a 1.0E+00 1.0E+00 9.9E‐01 1 655 78% 7.9E‐01 9.5E‐01 4.8E‐01

miR‐374ab‐5p 1.0E+00 1.0E+00 9.9E‐01 1 678 71% 9.5E‐01 9.7E‐01 5.2E‐01

miR‐137 1.0E+00 1.0E+00 1.0E+00 1 1144 77% 9.8E‐01 1.0E+00 9.8E‐01


37


eTable 9: Functional annotation of genes regulated by the top-10 miRNA – bio-logical processes. The following table contains a DAVID analysis showing enrichment of GO biological processes for genes targeted by two or more of the top ten conserved miRNA (Table 1). Only the hundred most significant processes are shown. “FE” is fold enrichment. The list of all genes in the categories can be obtained from the authors by request.

Top 10 miRNA GO Biological Process Count % P‐value List Total

Pop Hits

Pop Total FE

Benja‐mini

regulation of transcription 388 22 2.2E‐22 1303 2601 13528 1.5 7.4E‐19regulation of transcription from RNA polymerase II promoter 150 9 4.0E‐20 1303 727 13528 2.1 6.6E‐17positive regulation of transcription 123 7 1.5E‐18 1303 564 13528 2.3 1.7E‐15positive regulation of transcription, DNA‐dependent 110 6 1.7E‐18 1303 477 13528 2.4 1.4E‐15positive regulation of RNA metabolic process 110 6 3.3E‐18 1303 481 13528 2.4 2.2E‐15positive regulation of gene expression 124 7 6.7E‐18 1303 581 13528 2.2 3.7E‐15positive regulation of nucleobase, nucleoside, nucleotide and nu‐cleic acid metabolic process

130 8 7.6E‐18 1303 624 13528 2.2 3.6E‐15

positive regulation of macromolecule biosynthetic process 133 8 2.4E‐17 1303 654 13528 2.1 1.0E‐14positive regulation of nitrogen compound metabolic process 130 8 2.2E‐16 1303 644 13528 2.1 8.2E‐14positive regulation of biosynthetic process 136 8 4.9E‐16 1303 695 13528 2.0 1.5E‐13positive regulation of cellular biosynthetic process 134 8 8.0E‐16 1303 685 13528 2.0 2.3E‐13transcription 307 18 1.4E‐15 1303 2101 13528 1.5 4.0E‐13negative regulation of gene expression 108 6 1.4E‐15 1303 504 13528 2.2 3.7E‐13negative regulation of transcription 101 6 2.1E‐15 1303 459 13528 2.3 5.0E‐13regulation of RNA metabolic process 270 16 1.4E‐14 1303 1813 13528 1.5 3.0E‐12positive regulation of transcription from RNA polymerase II pro‐moter

85 5 4.2E‐14 1303 371 13528 2.4 8.7E‐12

positive regulation of macromolecule metabolic process 152 9 4.5E‐14 1303 857 13528 1.8 8.8E‐12negative regulation of macromolecule biosynthetic process 110 6 6.7E‐14 1303 547 13528 2.1 1.2E‐11regulation of transcription, DNA‐dependent 260 15 3.2E‐13 1303 1773 13528 1.5 5.5E‐11negative regulation of cellular biosynthetic process 110 6 3.8E‐13 1303 561 13528 2.0 6.3E‐11negative regulation of biosynthetic process 111 6 6.8E‐13 1303 573 13528 2.0 1.1E‐10protein amino acid phosphorylation 123 7 1.2E‐12 1303 667 13528 1.9 1.8E‐10negative regulation of transcription, DNA‐dependent 79 5 2.1E‐12 1303 356 13528 2.3 3.0E‐10negative regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolic process

101 6 2.7E‐12 1303 512 13528 2.0 3.8E‐10

negative regulation of RNA metabolic process 79 5 5.1E‐12 1303 362 13528 2.3 6.8E‐10negative regulation of nitrogen compound metabolic process 101 6 6.4E‐12 1303 519 13528 2.0 8.1E‐10phosphorus metabolic process 157 9 4.2E‐11 1303 973 13528 1.7 5.1E‐09phosphate metabolic process 157 9 4.2E‐11 1303 973 13528 1.7 5.1E‐09neuron development 72 4 1.9E‐10 1303 339 13528 2.2 2.2E‐08enzyme linked receptor protein signaling pathway 72 4 2.8E‐10 1303 342 13528 2.2 3.2E‐08cell morphogenesis 73 4 7.1E‐10 1303 356 13528 2.1 7.8E‐08negative regulation of macromolecule metabolic process 123 7 7.4E‐10 1303 734 13528 1.7 7.9E‐08cell morphogenesis involved in differentiation 56 3 1.3E‐09 1303 244 13528 2.4 1.4E‐07cell motion 88 5 2.2E‐09 1303 475 13528 1.9 2.2E‐07neuron differentiation 83 5 2.3E‐09 1303 438 13528 2.0 2.2E‐07cell migration 60 3 2.9E‐09 1303 276 13528 2.3 2.7E‐07cell projection organization 73 4 3.2E‐09 1303 368 13528 2.1 3.0E‐07negative regulation of transcription from RNA polymerase II pro‐moter

58 3 4.9E‐09 1303 266 13528 2.3 4.3E‐07

neuron projection morphogenesis 50 3 5.2E‐09 1303 213 13528 2.4 4.5E‐07tube development 51 3 5.6E‐09 1303 220 13528 2.4 4.7E‐07chordate embryonic development 67 4 6.7E‐09 1303 331 13528 2.1 5.5E‐07forebrain development 40 2 7.7E‐09 1303 152 13528 2.7 6.2E‐07cell morphogenesis involved in neuron differentiation 49 3 7.8E‐09 1303 209 13528 2.4 6.2E‐07neuron projection development 56 3 8.2E‐09 1303 256 13528 2.3 6.3E‐07embryonic development ending in birth or egg hatching 67 4 9.7E‐09 1303 334 13528 2.1 7.3E‐07phosphorylation 127 7 1.2E‐08 1303 800 13528 1.6 8.5E‐07axonogenesis 46 3 1.4E‐08 1303 193 13528 2.5 1.0E‐06in utero embryonic development 43 2 2.1E‐08 1303 176 13528 2.5 1.5E‐06cell junction organization 22 1 2.7E‐08 1303 57 13528 4.0 1.9E‐06cell motility 62 4 2.9E‐08 1303 307 13528 2.1 1.9E‐06


38


Top 10 miRNA GO Biological Process Count % P‐value List Total

Pop Hits

Pop Total FE

Benja‐mini

localization of cell 62 4 2.9E‐08 1303 307 13528 2.1 1.9E‐06cell projection morphogenesis 53 3 3.2E‐08 1303 245 13528 2.2 2.1E‐06cellular component morphogenesis 74 4 3.8E‐08 1303 397 13528 1.9 2.5E‐06cell part morphogenesis 54 3 5.7E‐08 1303 256 13528 2.2 3.6E‐06transmembrane receptor protein tyrosine kinase signaling pathway 49 3 7.9E‐08 1303 224 13528 2.3 5.0E‐06intracellular signaling cascade 177 10 9.1E‐08 1303 1256 13528 1.5 5.6E‐06heart development 46 3 4.1E‐07 1303 215 13528 2.2 2.5E‐05respiratory system development 29 2 7.8E‐07 1303 108 13528 2.8 4.6E‐05chromatin modification 53 3 1.3E‐06 1303 274 13528 2.0 7.6E‐05cell‐cell junction organization 15 1 1.8E‐06 1303 35 13528 4.4 1.0E‐04embryonic morphogenesis 57 3 1.9E‐06 1303 307 13528 1.9 1.1E‐04camera‐type eye development 28 2 2.2E‐06 1303 107 13528 2.7 1.2E‐04pattern specification process 51 3 3.1E‐06 1303 267 13528 2.0 1.7E‐04palate development 14 1 3.5E‐06 1303 32 13528 4.5 1.8E‐04regulation of cell migration 37 2 3.8E‐06 1303 169 13528 2.3 2.0E‐04regulation of cell proliferation 115 7 4.5E‐06 1303 787 13528 1.5 2.3E‐04protein kinase cascade 64 4 4.9E‐06 1303 370 13528 1.8 2.5E‐04regulation of cell motion 40 2 5.8E‐06 1303 193 13528 2.2 2.9E‐04proteolysis involved in cellular protein catabolic process 92 5 6.9E‐06 1303 600 13528 1.6 3.4E‐04cellular protein catabolic process 92 5 8.4E‐06 1303 603 13528 1.6 4.1E‐04regulation of phosphate metabolic process 77 4 1.3E‐05 1303 485 13528 1.6 6.0E‐04regulation of phosphorus metabolic process 77 4 1.3E‐05 1303 485 13528 1.6 6.0E‐04regulation of locomotion 39 2 1.3E‐05 1303 192 13528 2.1 6.0E‐04cell junction assembly 15 1 1.6E‐05 1303 41 13528 3.8 7.4E‐04lung development 25 1 1.6E‐05 1303 99 13528 2.6 7.5E‐04positive regulation of kinase activity 44 3 1.7E‐05 1303 231 13528 2.0 7.9E‐04eye development 30 2 1.7E‐05 1303 132 13528 2.4 7.8E‐04modification‐dependent protein catabolic process 87 5 2.0E‐05 1303 574 13528 1.6 8.7E‐04modification‐dependent macromolecule catabolic process 87 5 2.0E‐05 1303 574 13528 1.6 8.7E‐04positive regulation of transferase activity 45 3 2.1E‐05 1303 240 13528 1.9 9.0E‐04axon guidance 26 2 2.2E‐05 1303 107 13528 2.5 9.3E‐04insulin receptor signaling pathway 14 1 2.2E‐05 1303 37 13528 3.9 9.5E‐04regulation of kinase activity 60 3 2.5E‐05 1303 357 13528 1.7 1.0E‐03MAPKKK cascade 37 2 2.7E‐05 1303 184 13528 2.1 1.1E‐03respiratory tube development 25 1 2.8E‐05 1303 102 13528 2.5 1.1E‐03protein catabolic process 92 5 2.9E‐05 1303 622 13528 1.5 1.1E‐03response to hormone stimulus 61 4 2.9E‐05 1303 367 13528 1.7 1.2E‐03vasculature development 46 3 3.0E‐05 1303 251 13528 1.9 1.2E‐03appendage development 25 1 3.3E‐05 1303 103 13528 2.5 1.3E‐03limb development 25 1 3.3E‐05 1303 103 13528 2.5 1.3E‐03regulation of protein kinase activity 58 3 3.4E‐05 1303 345 13528 1.7 1.3E‐03regulation of phosphorylation 73 4 3.4E‐05 1303 466 13528 1.6 1.3E‐03blood vessel development 45 3 3.5E‐05 1303 245 13528 1.9 1.3E‐03positive regulation of protein kinase activity 42 2 3.6E‐05 1303 223 13528 2.0 1.4E‐03chromatin organization 62 4 3.7E‐05 1303 378 13528 1.7 1.4E‐03BMP signaling pathway 15 1 3.9E‐05 1303 44 13528 3.5 1.4E‐03regulation of transferase activity 61 4 4.4E‐05 1303 372 13528 1.7 1.6E‐03cell fate commitment 30 2 4.8E‐05 1303 139 13528 2.2 1.7E‐03appendage morphogenesis 24 1 5.0E‐05 1303 99 13528 2.5 1.8E‐03limb morphogenesis 24 1 5.0E‐05 1303 99 13528 2.5 1.8E‐03


39


eTable 10: Functional annotation of genes regulated by the top-10 miRNA – annotation clusters. The following table contains a DAVID analysis showing enrichment of functional clusters for genes targeted by two or more of the top ten conserved miRNA (Table 1). Only the ten most significant annotation clusters are shown. “FE” is fold enrichment. The list of all genes in the categories can be obtained from the authors by request. Top 10 miRNA Annotation clusters Score/Term Count % P‐value

List Total

Pop Hits

Pop Total FE

Benja‐mini

Annotation Cluster 1 Enrichment Score: 15.9 GOTERM_BP_FAT regulation of transcription 388 23 2.2E‐22 1303 2601 13528 1.6 7.4E‐19GOTERM_MF_FAT transcription regulator activity 267 16 3.5E‐22 1309 1512 12983 1.8 3.6E‐19SP_PIR_KEYWORDS transcription regulation 305 18 1.9E‐21 1722 2026 19235 1.7 3.3E‐19SP_PIR_KEYWORDS nucleus 543 31 4.1E‐21 1722 4283 19235 1.4 5.4E‐19SP_PIR_KEYWORDS Transcription 306 18 2.8E‐20 1722 2071 19235 1.7 2.9E‐18GOTERM_MF_FAT transcription factor activity 179 10 4.3E‐16 1309 975 12983 1.8 2.3E‐13GOTERM_BP_FAT transcription 307 18 1.4E‐15 1303 2101 13528 1.5 4.0E‐13GOTERM_BP_FAT regulation of RNA metabolic process 270 16 1.4E‐14 1303 1813 13528 1.6 3.0E‐12GOTERM_BP_FAT regulation of transcription, DNA‐dependent 260 15 3.2E‐13 1303 1773 13528 1.5 5.5E‐11SP_PIR_KEYWORDS dna‐binding 254 15 3.1E‐12 1722 1868 19235 1.5 1.5E‐10GOTERM_MF_FAT sequence‐specific DNA binding 115 7 2.1E‐11 1309 607 12983 1.9 7.2E‐09GOTERM_MF_FAT DNA binding 314 18 5.8E‐09 1309 2331 12983 1.3 1.0E‐06 Annotation Cluster 2 Enrichment Score: 15.6 GOTERM_MF_FAT transcription regulator activity 267 16 3.5E‐22 1309 1512 12983 1.8 3.6E‐19GOTERM_BP_FAT regulation of transcription from RNA polymerase II promoter150 9 4.0E‐20 1303 727 13528 2.1 6.6E‐17SP_PIR_KEYWORDS activator 112 7 1.4E‐18 1722 520 19235 2.4 1.2E‐16GOTERM_BP_FAT positive regulation of transcription 123 7 1.5E‐18 1303 564 13528 2.3 1.7E‐15GOTERM_BP_FAT positive regulation of transcription, DNA‐dependent 110 6 1.7E‐18 1303 477 13528 2.4 1.4E‐15GOTERM_BP_FAT positive regulation of RNA metabolic process 110 6 3.3E‐18 1303 481 13528 2.4 2.2E‐15GOTERM_BP_FAT positive regulation of gene expression 124 7 6.7E‐18 1303 581 13528 2.2 3.7E‐15GOTERM_BP_FAT positive regulation of nucleobase, nucleoside, nucleotide

and nucleic acid metabolic process 130 8 7.6E‐18 1303 624 13528 2.2 3.6E‐15

GOTERM_BP_FAT positive regulation of macromolecule biosynthetic process 133 8 2.4E‐17 1303 654 13528 2.1 1.0E‐14GOTERM_BP_FAT positive regulation of nitrogen compound metabolic process 130 8 2.2E‐16 1303 644 13528 2.1 8.2E‐14GOTERM_BP_FAT positive regulation of biosynthetic process 136 8 4.9E‐16 1303 695 13528 2.0 1.5E‐13GOTERM_BP_FAT positive regulation of cellular biosynthetic process 134 8 8.0E‐16 1303 685 13528 2.0 2.3E‐13GOTERM_BP_FAT regulation of RNA metabolic process 270 16 1.4E‐14 1303 1813 13528 1.6 3.0E‐12GOTERM_BP_FAT positive regulation of transcription from RNA polymerase II

promoter 85 5 4.2E‐14 1303 371 13528 2.4 8.7E‐12

GOTERM_BP_FAT positive regulation of macromolecule metabolic process 152 9 4.5E‐14 1303 857 13528 1.8 8.8E‐12GOTERM_BP_FAT regulation of transcription, DNA‐dependent 260 15 3.2E‐13 1303 1773 13528 1.5 5.5E‐11SP_PIR_KEYWORDS dna‐binding 254 15 3.1E‐12 1722 1868 19235 1.5 1.5E‐10GOTERM_MF_FAT transcription activator activity 80 5 8.9E‐09 1309 410 12983 1.9 1.0E‐06 Annotation Cluster 3 Enrichment Score: 12.3 GOTERM_BP_FAT regulation of transcription from RNA polymerase II promoter150 9 4.0E‐20 1303 727 13528 2.1 6.6E‐17GOTERM_BP_FAT negative regulation of gene expression 108 6 1.4E‐15 1303 504 13528 2.2 3.7E‐13GOTERM_BP_FAT negative regulation of transcription 101 6 2.1E‐15 1303 459 13528 2.3 5.0E‐13GOTERM_BP_FAT negative regulation of macromolecule biosynthetic process 110 6 6.7E‐14 1303 547 13528 2.1 1.2E‐11GOTERM_BP_FAT negative regulation of cellular biosynthetic process 110 6 3.8E‐13 1303 561 13528 2.0 6.3E‐11GOTERM_BP_FAT negative regulation of biosynthetic process 111 6 6.8E‐13 1303 573 13528 2.0 1.1E‐10GOTERM_BP_FAT negative regulation of transcription, DNA‐dependent 79 5 2.1E‐12 1303 356 13528 2.3 3.0E‐10GOTERM_BP_FAT negative regulation of nucleobase, nucleoside, nucleotide

and nucleic acid metabolic process 101 6 2.7E‐12 1303 512 13528 2.1 3.8E‐10

GOTERM_BP_FAT negative regulation of RNA metabolic process 79 5 5.1E‐12 1303 362 13528 2.3 6.8E‐10GOTERM_BP_FAT negative regulation of nitrogen compound metabolic pro‐

cess 101 6 6.4E‐12 1303 519 13528 2.0 8.1E‐10

GOTERM_MF_FAT transcription repressor activity 72 4 4.9E‐11 1309 316 12983 2.3 1.3E‐08GOTERM_BP_FAT negative regulation of macromolecule metabolic process 123 7 7.5E‐10 1303 734 13528 1.7 8.0E‐08GOTERM_BP_FAT negative regulation of transcription from RNA polymerase II

promoter 58 3 4.9E‐09 1303 266 13528 2.3 4.4E‐07

Annotation Cluster 4 Enrichment Score: 8.07 GOTERM_BP_FAT cell motion 88 5 2.2E‐09 1303 475 13528 1.9 2.2E‐07GOTERM_BP_FAT cell migration 60 4 2.9E‐09 1303 276 13528 2.3 2.7E‐07GOTERM_BP_FAT localization of cell 62 4 2.9E‐08 1303 307 13528 2.1 1.9E‐06GOTERM_BP_FAT cell motility 62 4 2.9E‐08 1303 307 13528 2.1 1.9E‐06


40


Top 10 miRNA Annotation clusters Score/Term Count % P‐value

List Total

Pop Hits

Pop Total FE

Benja‐mini

Annotation Cluster 5 Enrichment Score: 8.00 GOTERM_BP_FAT neuron development 72 4 1.9E‐10 1303 339 13528 2.2 2.2E‐08GOTERM_BP_FAT cell morphogenesis 73 4 7.1E‐10 1303 356 13528 2.1 7.8E‐08GOTERM_BP_FAT cell morphogenesis involved in differentiation 56 3 1.3E‐09 1303 244 13528 2.4 1.4E‐07GOTERM_BP_FAT neuron differentiation 83 5 2.3E‐09 1303 438 13528 2.0 2.2E‐07GOTERM_BP_FAT cell projection organization 73 4 3.2E‐09 1303 368 13528 2.1 3.0E‐07GOTERM_BP_FAT neuron projection morphogenesis 50 3 5.2E‐09 1303 213 13528 2.4 4.5E‐07GOTERM_BP_FAT cell morphogenesis involved in neuron differentiation 49 3 7.8E‐09 1303 209 13528 2.4 6.2E‐07GOTERM_BP_FAT neuron projection development 56 3 8.2E‐09 1303 256 13528 2.3 6.3E‐07GOTERM_BP_FAT axonogenesis 46 3 1.4E‐08 1303 193 13528 2.5 1.0E‐06GOTERM_BP_FAT cell projection morphogenesis 53 3 3.2E‐08 1303 245 13528 2.3 2.1E‐06GOTERM_BP_FAT cellular component morphogenesis 74 4 3.8E‐08 1303 397 13528 1.9 2.5E‐06GOTERM_BP_FAT cell part morphogenesis 54 3 5.7E‐08 1303 256 13528 2.2 3.6E‐06GOTERM_BP_FAT axon guidance 26 2 2.2E‐05 1303 107 13528 2.5 9.3E‐04 Annotation Cluster 6 Enrichment Score: 7.45 GOTERM_CC_FAT synapse 69 4 3.2E‐10 1114 355 12782 2.2 1.7E‐07GOTERM_CC_FAT cell junction 88 5 1.2E‐09 1114 518 12782 2.0 3.2E‐07SP_PIR_KEYWORDS cell junction 67 4 7.4E‐07 1722 399 19235 1.9 1.6E‐05SP_PIR_KEYWORDS synapse 41 2 5.2E‐06 1722 213 19235 2.2 1.1E‐04 Annotation Cluster 7 Enrichment Score: 7.4 GOTERM_BP_FAT chordate embryonic development 67 4 6.7E‐09 1303 331 13528 2.1 5.5E‐07GOTERM_BP_FAT embryonic development ending in birth or egg hatching 67 4 9.7E‐09 1303 334 13528 2.1 7.3E‐07GOTERM_BP_FAT in utero embryonic development 43 3 2.1E‐08 1303 176 13528 2.5 1.5E‐06GOTERM_BP_FAT embryonic morphogenesis 57 3 1.9E‐06 1303 307 13528 1.9 1.1E‐04 Annotation Cluster 8 Enrichment Score: 7.4 SP_PIR_KEYWORDS zinc‐finger 248 14 7.7E‐15 1722 1718 19235 1.6 5.1E‐13SP_PIR_KEYWORDS metal‐binding 370 21 2.9E‐12 1722 2972 19235 1.4 1.5E‐10SP_PIR_KEYWORDS zinc 288 17 3.4E‐12 1722 2189 19235 1.5 1.5E‐10GOTERM_MF_FAT zinc ion binding 295 17 3.3E‐06 1309 2311 12983 1.3 2.6E‐04GOTERM_MF_FAT metal ion binding 485 28 1.9E‐05 1309 4140 12983 1.2 1.3E‐03GOTERM_MF_FAT cation binding 485 28 5.7E‐05 1309 4179 12983 1.2 3.5E‐03GOTERM_MF_FAT ion binding 490 28 8.3E‐05 1309 4241 12983 1.2 4.1E‐03GOTERM_MF_FAT transition metal ion binding 331 19 3.4E‐04 1309 2785 12983 1.2 1.5E‐02 Annotation Cluster 9 Enrichment Score: 6.77 GOTERM_BP_FAT protein amino acid phosphorylation 123 7 1.2E‐12 1303 667 13528 1.9 1.8E‐10SP_PIR_KEYWORDS serine/threonine‐protein kinase 78 5 6.9E‐12 1722 381 19235 2.3 2.8E‐10INTERPRO Serine/threonine protein kinase, active site 76 4 1.4E‐11 1574 354 16659 2.3 2.5E‐08SP_PIR_KEYWORDS kinase 116 7 2.9E‐11 1722 688 19235 1.9 1.1E‐09GOTERM_BP_FAT phosphate metabolic process 157 9 4.2E‐11 1303 973 13528 1.7 5.2E‐09GOTERM_BP_FAT phosphorus metabolic process 157 9 4.2E‐11 1303 973 13528 1.7 5.2E‐09INTERPRO Protein kinase, ATP binding site 89 5 4.4E‐11 1574 455 16659 2.1 3.8E‐08INTERPRO Serine/threonine protein kinase‐related 75 4 7.7E‐11 1574 359 16659 2.2 4.4E‐08INTERPRO Serine/threonine protein kinase 60 4 1.1E‐10 1574 259 16659 2.5 4.8E‐08UP_SEQ_FEATURE domain:Protein kinase 86 5 2.9E‐10 1722 469 19113 2.0 1.4E‐07INTERPRO Protein kinase, core 89 5 4.9E‐10 1574 476 16659 2.0 1.7E‐07UP_SEQ_FEATURE binding site:ATP 93 5 1.8E‐09 1722 542 19113 1.9 7.2E‐07GOTERM_MF_FAT protein kinase activity 107 6 7.0E‐09 1309 606 12983 1.8 9.1E‐07GOTERM_BP_FAT phosphorylation 127 7 1.2E‐08 1303 800 13528 1.7 8.5E‐07GOTERM_MF_FAT protein serine/threonine kinase activity 81 5 3.6E‐08 1309 430 12983 1.9 3.8E‐06SP_PIR_KEYWORDS atp‐binding 175 10 1.1E‐07 1722 1326 19235 1.5 3.1E‐06SP_PIR_KEYWORDS nucleotide‐binding 212 12 1.9E‐07 1722 1686 19235 1.4 4.8E‐06SP_PIR_KEYWORDS transferase 180 10 3.1E‐07 1722 1394 19235 1.4 7.6E‐06SMART S_TKc 60 4 6.8E‐07 1095 259 9079 1.9 2.4E‐04UP_SEQ_FEATURE nucleotide phosphate‐binding region:ATP 130 8 2.3E‐06 1722 962 19113 1.5 5.5E‐04UP_SEQ_FEATURE active site:Proton acceptor 92 5 2.3E‐05 1722 658 19113 1.6 4.2E‐03GOTERM_MF_FAT nucleotide binding 270 16 6.8E‐04 1309 2245 12983 1.2 2.4E‐02GOTERM_MF_FAT adenyl ribonucleotide binding 183 11 3.1E‐03 1309 1497 12983 1.2 8.5E‐02GOTERM_MF_FAT ATP binding 180 10 3.9E‐03 1309 1477 12983 1.2 9.4E‐02GOTERM_MF_FAT purine ribonucleotide binding 216 13 7.8E‐03 1309 1836 12983 1.2 1.5E‐01GOTERM_MF_FAT ribonucleotide binding 216 13 7.8E‐03 1309 1836 12983 1.2 1.5E‐01GOTERM_MF_FAT adenyl nucleotide binding 187 11 9.7E‐03 1309 1577 12983 1.2 1.6E‐01GOTERM_MF_FAT purine nucleoside binding 189 11 1.1E‐02 1309 1601 12983 1.2 1.7E‐01GOTERM_MF_FAT nucleoside binding 189 11 1.5E‐02 1309 1612 12983 1.2 2.0E‐01GOTERM_MF_FAT purine nucleotide binding 220 13 1.9E‐02 1309 1918 12983 1.1 2.5E‐01


41


Top 10 miRNA Annotation clusters Score/Term Count % P‐value

List Total

Pop Hits

Pop Total FE

Benja‐mini

Annotation Cluster 10 Enrichment Score: 5.93 GOTERM_BP_FAT tube development 51 3 5.6E‐09 1303 220 13528 2.4 4.7E‐07GOTERM_BP_FAT respiratory system development 29 2 7.8E‐07 1303 108 13528 2.8 4.6E‐05GOTERM_BP_FAT lung development 25 1 1.6E‐05 1303 99 13528 2.6 7.5E‐04GOTERM_BP_FAT respiratory tube development 25 1 2.8E‐05 1303 102 13528 2.5 1.1E‐03


42


eTable 11: The top 50 most schizophrenia-associated genes targeted by miR-9-5p. ”p-value” is the p-value of association of the most strongly associated variant located within the boundaries of the gene, and ”SNP” is the name of this variant. Note that these p-values are without taking the PGC2 replication into account and do not refer to the clump definition from PGC2 (see above). The list therefore might differ with regards to the published p-values from PGC2 for these genes. Entrez Gene p‐value SNP Description 54805 CNNM2 3.64E‐16 rs7913682 cyclin M2

23368 PPP1R13B 5.61E‐13 rs4906364 protein phosphatase 1, regulatory subunit 13B

5045 FURIN 2.30E‐12 rs4702 furin (paired basic amino acid cleaving enzyme)

57605 PITPNM2 1.63E‐11 rs12425850 phosphatidylinositol transfer protein, membrane‐associated 2

783 CACNB2 3.56E‐11 rs7893279 calcium channel, voltage‐dependent, beta 2 subunit

152330 CNTN4 4.87E‐11 rs17194490 contactin 4

55193 PBRM1 1.18E‐10 rs139364760 polybromo 1

55626 AMBRA1 1.26E‐10 rs61882743 autophagy/beclin‐1 regulator 1

8087 FXR1 1.56E‐10 rs1805579 fragile X mental retardation, autosomal homolog 1

51460 SFMBT1 1.56E‐10 rs2710313 Scm‐like with four mbt domains 1

55206 SBNO1 3.66E‐10 rs56197170 strawberry notch homolog 1 (Drosophila)

473 RERE 2.03E‐09 rs34269918 arginine‐glutamic acid dipeptide (RE) repeats

375346 TMEM110 2.95E‐09 rs6445541 transmembrane protein 110

1813 DRD2 1.45E‐08 rs4630328 dopamine receptor D2

4775 NFATC3 3.27E‐08 rs8044995 nuclear factor of activated T‐cells, cytoplasmic, calcineurin‐dependen t3

2309 FOXO3 3.37E‐08 rs9398171 forkhead box O3

4750 NEK1 4.25E‐08 rs5863995 NIMA‐related kinase 1

56924 PAK6 4.92E‐08 rs56205728 p21 protein (Cdc42/Rac)‐activated kinase 6

64506 CPEB1 5.52E‐08 15‐83303518 cytoplasmic polyadenylation element binding protein 1

83857 TMTC1 7.06E‐08 rs679087 transmembrane and tetratricopeptide repeat containing 1

27086 FOXP1 1.25E‐07 rs7372960 forkhead box P1

4208 MEF2C 1.39E‐07 rs1065861 myocyte enhancer factor 2C

25921 ZDHHC5 1.46E‐07 rs488769 zinc finger, DHHC‐type containing 5

22990 PCNX 1.59E‐07 rs67981189 pecanex homolog (Drosophila)

4325 MMP16 2.13E‐07 rs7837860 matrix metallopeptidase 16 (membrane‐inserted)

5520 PPP2R2A 2.27E‐07 rs11419341 protein phosphatase 2, regulatory subunit B, alpha

11278 KLF12 2.47E‐07 rs12877581 Kruppel‐like factor 12

23362 PSD3 2.66E‐07 rs6984438 pleckstrin and Sec7 domain containing 3

151011 SEPT10 2.83E‐07 rs58012425 septin 10

53335 BCL11A 3.11E‐07 rs7599488 B‐cell CLL/lymphoma 11A (zinc finger protein)

118980 SFXN2 3.54E‐07 rs11191379 sideroflexin 2

389421 LIN28B 3.60E‐07 rs78370910 lin‐28 homolog B (C, elegans)

22891 ZNF365 3.98E‐07 rs11598767 zinc finger protein 365

8658 TNKS 4.00E‐07 rs12541709 tankyrase, TRF1‐interacting ankyrin‐related ADP‐ribose polymerase

23334 SZT2 5.31E‐07 rs141508822 seizure threshold 2 homolog (mouse)

9568 GABBR2 5.48E‐07 rs2304389 gamma‐aminobutyric acid (GABA) B receptor, 2

10082 GPC6 7.07E‐07 rs9584154 glypican 6

4978 OPCML 8.38E‐07 rs2917569 opioid binding protein/cell adhesion molecule‐like

55512 SMPD3 1.07E‐06 rs8059916 sphingomyelin phosphodiesterase 3, neutral membrane

133418 EMB 1.15E‐06 rs62365899 embigin

4179 CD46 1.17E‐06 rs1142469 CD46 molecule, complement regulatory protein

9839 ZEB2 1.29E‐06 rs35015447 zinc finger E‐box binding homeobox 2

80114 BICC1 1.32E‐06 rs11006253 bicaudal C homolog 1 (Drosophila)

23259 DDHD2 1.56E‐06 rs9643870 DDHD domain containing 2

27303 RBMS3 1.70E‐06 rs6549963 RNA binding motif, single stranded interacting protein 3

253832 ZDHHC20 1.71E‐06 rs9316337 zinc finger, DHHC‐type containing 20

80059 LRRTM4 1.96E‐06 rs61712019 leucine rich repeat transmembrane neuronal 4

388336 SHISA6 2.13E‐06 rs2159292 shisa family member 6

794 CALB2 2.32E‐06 rs62055045 calbindin 2

57520 HECW2 2.41E‐06 rs9677260 HECT, C2 and WW domain containing E3 ubiquitin protein ligase 2


43


eTable 12: Functional annotation of genes regulated by miR-9-5p – biological processes. The following table contains a DAVID analysis showing enrichment of GO biological processes for genes targeted by miR-9-5p. Only the hundred most significant processes are shown. “FE” is fold enrichment. The list of all genes in the categories can be obtained from the authors by request.

miR‐9‐5p DAVID GO Biological Process annotation Count % P‐value List Total

Pop Hits

Pop Total FE

Benja‐mini

regulation of transcription 238 19 9.7E‐07 934 2601 13528 1.3 3.0E‐03negative regulation of gene expression 65 5 1.3E‐06 934 504 13528 1.9 2.0E‐03negative regulation of macromolecule biosynthetic process 69 6 1.3E‐06 934 547 13528 1.8 1.4E‐03cell motion 62 5 1.6E‐06 934 475 13528 1.9 1.3E‐03negative regulation of cell differentiation 36 3 1.8E‐06 934 216 13528 2.4 1.1E‐03cell migration 42 3 2.4E‐06 934 276 13528 2.2 1.3E‐03cell projection organization 51 4 2.9E‐06 934 368 13528 2.0 1.3E‐03regulation of transcription from RNA polymerase II promoter 84 7 3.0E‐06 934 727 13528 1.7 1.2E‐03regulation of RNA metabolic process 173 14 4.3E‐06 934 1813 13528 1.4 1.5E‐03negative regulation of transcription 59 5 4.9E‐06 934 459 13528 1.9 1.5E‐03cell morphogenesis 49 4 5.5E‐06 934 356 13528 2.0 1.6E‐03negative regulation of cellular biosynthetic process 68 6 6.4E‐06 934 561 13528 1.8 1.7E‐03negative regulation of biosynthetic process 69 6 6.7E‐06 934 573 13528 1.7 1.6E‐03tube development 35 3 7.4E‐06 934 220 13528 2.3 1.6E‐03cellular component morphogenesis 52 4 1.1E‐05 934 397 13528 1.9 2.4E‐03negative regulation of macromolecule metabolic process 82 7 1.4E‐05 934 734 13528 1.6 2.8E‐03cell motility 43 3 1.5E‐05 934 307 13528 2.0 2.7E‐03localization of cell 43 3 1.5E‐05 934 307 13528 2.0 2.7E‐03regulation of transcription, DNA‐dependent 165 13 3.3E‐05 934 1773 13528 1.3 5.7E‐03neuron differentiation 54 4 4.1E‐05 934 438 13528 1.8 6.8E‐03vesicle‐mediated transport 66 5 5.1E‐05 934 576 13528 1.7 7.9E‐03tube morphogenesis 23 2 5.2E‐05 934 127 13528 2.6 7.7E‐03negative regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolic process

60 5 6.4E‐05 934 512 13528 1.7 9.0E‐03

negative regulation of RNA metabolic process 46 4 8.3E‐05 934 362 13528 1.8 1.1E‐02negative regulation of nitrogen compound metabolic process 60 5 9.3E‐05 934 519 13528 1.7 1.2E‐02negative regulation of transcription, DNA‐dependent 45 4 1.1E‐04 934 356 13528 1.8 1.4E‐02neuron projection morphogenesis 31 3 1.4E‐04 934 213 13528 2.1 1.7E‐02neuron development 43 3 1.5E‐04 934 339 13528 1.8 1.7E‐02cell projection morphogenesis 34 3 1.6E‐04 934 245 13528 2.0 1.8E‐02neuron projection development 35 3 1.7E‐04 934 256 13528 2.0 1.8E‐02cell morphogenesis involved in neuron differentiation 30 2 2.4E‐04 934 209 13528 2.1 2.5E‐02protein amino acid phosphorylation 71 6 2.5E‐04 934 667 13528 1.5 2.4E‐02transcription 184 15 3.0E‐04 934 2101 13528 1.3 2.9E‐02cell morphogenesis involved in differentiation 33 3 3.3E‐04 934 244 13528 2.0 3.1E‐02axonogenesis 28 2 3.4E‐04 934 193 13528 2.1 3.1E‐02cell part morphogenesis 34 3 3.7E‐04 934 256 13528 1.9 3.2E‐02cell junction organization 13 1 4.2E‐04 934 57 13528 3.3 3.6E‐02intracellular transport 69 6 4.6E‐04 934 657 13528 1.5 3.8E‐02regulation of specific transcription from RNA polymerase II pro‐moter

17 1 6.5E‐04 934 94 13528 2.6 5.2E‐02

blood vessel development 32 3 7.6E‐04 934 245 13528 1.9 5.9E‐02vasculature development 32 3 1.1E‐03 934 251 13528 1.8 8.4E‐02positive regulation of transcription, DNA‐dependent 52 4 1.1E‐03 934 477 13528 1.6 8.2E‐02lysosomal transport 8 1 1.2E‐03 934 25 13528 4.6 8.2E‐02central nervous system neuron development 9 1 1.2E‐03 934 32 13528 4.1 8.2E‐02response to insulin stimulus 17 1 1.3E‐03 934 100 13528 2.5 8.7E‐02chordate embryonic development 39 3 1.3E‐03 934 331 13528 1.7 8.8E‐02central nervous system neuron differentiation 10 1 1.3E‐03 934 40 13528 3.6 8.6E‐02positive regulation of RNA metabolic process 52 4 1.4E‐03 934 481 13528 1.6 8.6E‐02negative regulation of transcription from RNA polymerase II pro‐moter

33 3 1.5E‐03 934 266 13528 1.8 9.0E‐02

embryonic development ending in birth or egg hatching 39 3 1.6E‐03 934 334 13528 1.7 9.5E‐02cell junction assembly 10 1 1.6E‐03 934 41 13528 3.5 9.5E‐02membrane organization 43 3 1.7E‐03 934 381 13528 1.6 9.8E‐02


44


miR‐9‐5p DAVID GO Biological Process annotation Count % P‐value List Total

Pop Hits

Pop Total FE

Benja‐mini

positive regulation of transcription from RNA polymerase II pro‐moter

42 3 1.8E‐03 934 371 13528 1.6 1.0E‐01

regulation of gene‐specific transcription 20 2 2.1E‐03 934 134 13528 2.2 1.2E‐01in utero embryonic development 24 2 2.3E‐03 934 176 13528 2.0 1.2E‐01chromatin modification 33 3 2.3E‐03 934 274 13528 1.7 1.2E‐01cellular protein localization 45 4 2.3E‐03 934 411 13528 1.6 1.2E‐01hindbrain development 12 1 2.4E‐03 934 60 13528 2.9 1.2E‐01protein transport 74 6 2.4E‐03 934 762 13528 1.4 1.2E‐01endocytosis 28 2 2.5E‐03 934 220 13528 1.8 1.2E‐01membrane invagination 28 2 2.5E‐03 934 220 13528 1.8 1.2E‐01regulation of Ras protein signal transduction 27 2 2.6E‐03 934 210 13528 1.9 1.3E‐01striated muscle cell differentiation 15 1 2.7E‐03 934 88 13528 2.5 1.3E‐01positive regulation of gene expression 59 5 2.7E‐03 934 581 13528 1.5 1.3E‐01cellular macromolecule localization 45 4 2.7E‐03 934 414 13528 1.6 1.2E‐01blood vessel morphogenesis 27 2 2.8E‐03 934 211 13528 1.9 1.3E‐01positive regulation of nitrogen compound metabolic process 64 5 2.9E‐03 934 644 13528 1.4 1.3E‐01establishment of protein localization 74 6 3.0E‐03 934 769 13528 1.4 1.3E‐01protein localization 83 7 3.1E‐03 934 882 13528 1.4 1.3E‐01positive regulation of biosynthetic process 68 6 3.2E‐03 934 695 13528 1.4 1.3E‐01positive regulation of cellular biosynthetic process 67 5 3.3E‐03 934 685 13528 1.4 1.4E‐01proteolysis involved in cellular protein catabolic process 60 5 3.4E‐03 934 600 13528 1.4 1.4E‐01positive regulation of nucleobase, nucleoside, nucleotide and nu‐cleic acid metabolic process

62 5 3.4E‐03 934 624 13528 1.4 1.4E‐01

positive regulation of transcription 57 5 3.5E‐03 934 564 13528 1.5 1.4E‐01myotube differentiation 6 0 3.6E‐03 934 16 13528 5.4 1.4E‐01lamellipodium assembly 6 0 3.6E‐03 934 16 13528 5.4 1.4E‐01cell adhesion 68 6 3.7E‐03 934 700 13528 1.4 1.4E‐01small GTPase mediated signal transduction 35 3 3.7E‐03 934 305 13528 1.7 1.4E‐01morphogenesis of an epithelium 16 1 3.8E‐03 934 101 13528 2.3 1.4E‐01biological adhesion 68 6 3.8E‐03 934 701 13528 1.4 1.4E‐01muscle cell differentiation 18 1 3.9E‐03 934 121 13528 2.2 1.4E‐01cellular protein catabolic process 60 5 3.9E‐03 934 603 13528 1.4 1.4E‐01cell‐substrate junction assembly 7 1 3.9E‐03 934 23 13528 4.4 1.4E‐01positive regulation of macromolecule biosynthetic process 64 5 4.1E‐03 934 654 13528 1.4 1.5E‐01enzyme linked receptor protein signaling pathway 38 3 4.2E‐03 934 342 13528 1.6 1.5E‐01cell projection assembly 14 1 4.3E‐03 934 83 13528 2.4 1.5E‐01sphingolipid biosynthetic process 8 1 4.4E‐03 934 31 13528 3.7 1.5E‐01morphogenesis of a branching structure 13 1 4.5E‐03 934 74 13528 2.5 1.5E‐01response to peptide hormone stimulus 21 2 4.6E‐03 934 154 13528 2.0 1.5E‐01ubiquitin cycle 7 1 4.9E‐03 934 24 13528 4.2 1.6E‐01positive regulation of specific transcription from RNA polymerase II promoter

11 1 5.2E‐03 934 57 13528 2.8 1.7E‐01

vacuolar transport 8 1 5.3E‐03 934 32 13528 3.6 1.7E‐01palate development 8 1 5.3E‐03 934 32 13528 3.6 1.7E‐01epithelial tube morphogenesis 12 1 5.8E‐03 934 67 13528 2.6 1.8E‐01regulation of vesicle‐mediated transport 15 1 6.0E‐03 934 96 13528 2.3 1.8E‐01intracellular protein transport 40 3 6.2E‐03 934 374 13528 1.5 1.9E‐01negative regulation of specific transcription from RNA polymerase II promoter

9 1 6.2E‐03 934 41 13528 3.2 1.9E‐01

transmembrane receptor protein tyrosine kinase signaling pathway 27 2 6.3E‐03 934 224 13528 1.7 1.9E‐01angiogenesis 20 2 6.4E‐03 934 148 13528 2.0 1.9E‐01negative regulation of neuron differentiation 8 1 6.4E‐03 934 33 13528 3.5 1.9E‐01


45


eTable 13: Functional annotation of genes regulated by miR-9-5p – annotation clusters. The following table contains a DAVID analysis showing enrichment of functional clusters for genes targeted miR-9-5p. Only the ten most significant annotation clusters are shown. “FE” is fold enrichment. The list of all genes in the categories can be obtained from the authors by request. miR‐9‐5p Annotation clusters Term Count % P‐value

List Total

Pop Hits

Pop Total FE

Benja‐mini

Annotation Cluster 1 Enrichment Score: 5.58 SP_PIR_KEYWORDS metal‐binding 266 22 2.9E‐09 1231 2972 19235 1.40 4.7E‐07SP_PIR_KEYWORDS zinc 202 16 4.5E‐08 1231 2189 19235 1.44 4.4E‐06SP_PIR_KEYWORDS zinc‐finger 163 13 2.1E‐07 1231 1718 19235 1.48 1.2E‐05GOTERM_MF_FAT metal ion binding 354 29 9.1E‐06 921 4140 12983 1.21 2.9E‐03GOTERM_MF_FAT ion binding 361 29 1.1E‐05 921 4241 12983 1.20 2.6E‐03GOTERM_MF_FAT cation binding 354 29 2.3E‐05 921 4179 12983 1.19 3.7E‐03GOTERM_MF_FAT zinc ion binding 209 17 6.8E‐05 921 2311 12983 1.27 9.3E‐03GOTERM_MF_FAT transition metal ion binding 239 19 5.3E‐04 921 2785 12983 1.21 4.6E‐02 Annotation Cluster 2 Enrichment Score: 5.26 GOTERM_BP_FAT cell motion 62 5 1.6E‐06 934 475 13528 1.89 1.3E‐03GOTERM_BP_FAT cell migration 42 3 2.4E‐06 934 276 13528 2.20 1.3E‐03GOTERM_BP_FAT localization of cell 43 4 1.5E‐05 934 307 13528 2.03 2.7E‐03GOTERM_BP_FAT cell motility 43 4 1.5E‐05 934 307 13528 2.03 2.7E‐03 Annotation Cluster 3 Enrichment Score: 5.25 GOTERM_CC_FAT basolateral plasma membrane 35 3 2.7E‐07 829 203 12782 2.66 4.4E‐05GOTERM_CC_FAT adherens junction 29 2 6.4E‐07 829 155 12782 2.88 7.7E‐05GOTERM_CC_FAT anchoring junction 29 2 5.4E‐06 829 172 12782 2.60 4.3E‐04GOTERM_CC_FAT focal adhesion 20 2 2.6E‐05 829 102 12782 3.02 1.2E‐03GOTERM_CC_FAT cell‐substrate junction 21 2 3.0E‐05 829 112 12782 2.89 1.3E‐03GOTERM_CC_FAT cell‐substrate adherens junction 20 2 4.5E‐05 829 106 12782 2.91 1.8E‐03 Annotation Cluster 4 Enrichment Score: 5.24 SP_PIR_KEYWORDS nucleus 354 29 3.1E‐08 1231 4283 19235 1.29 3.8E‐06GOTERM_MF_FAT transcription regulator activity 161 13 6.1E‐08 921 1512 12983 1.50 5.9E‐05SP_PIR_KEYWORDS transcription regulation 184 15 6.4E‐07 1231 2026 19235 1.42 3.1E‐05GOTERM_BP_FAT regulation of transcription 238 19 9.7E‐07 934 2601 13528 1.33 3.0E‐03SP_PIR_KEYWORDS Transcription 184 15 2.6E‐06 1231 2071 19235 1.39 1.1E‐04GOTERM_BP_FAT regulation of RNA metabolic process 173 14 4.3E‐06 934 1813 13528 1.38 1.5E‐03GOTERM_MF_FAT transcription factor activity 104 8 2.0E‐05 921 975 12983 1.50 3.9E‐03GOTERM_BP_FAT regulation of transcription, DNA‐dependent 165 13 3.3E‐05 934 1773 13528 1.35 5.7E‐03SP_PIR_KEYWORDS dna‐binding 161 13 6.3E‐05 1231 1868 19235 1.35 1.5E‐03GOTERM_BP_FAT transcription 184 15 3.0E‐04 934 2101 13528 1.27 2.9E‐02GOTERM_MF_FAT DNA binding 201 16 1.4E‐03 921 2331 12983 1.22 9.1E‐02 Annotation Cluster 5 Enrichment Score: 5.04 GOTERM_CC_FAT Golgi apparatus 94 8 9.1E‐07 829 872 12782 1.66 8.7E‐05SP_PIR_KEYWORDS golgi apparatus 66 5 1.1E‐05 1231 588 19235 1.75 3.9E‐04GOTERM_CC_FAT Golgi apparatus part 38 3 7.7E‐05 829 294 12782 1.99 2.6E‐03 Annotation Cluster 6 Enrichment Score: 4.80 SP_PIR_KEYWORDS repressor 59 5 8.3E‐08 1231 435 19235 2.12 5.8E‐06GOTERM_BP_FAT negative regulation of gene expression 65 5 1.3E‐06 934 504 13528 1.87 2.1E‐03GOTERM_BP_FAT negative regulation of macromolecule biosynthetic process 69 6 1.3E‐06 934 547 13528 1.83 1.4E‐03GOTERM_BP_FAT negative regulation of transcription 59 5 4.9E‐06 934 459 13528 1.86 1.5E‐03GOTERM_BP_FAT negative regulation of cellular biosynthetic process 68 6 6.4E‐06 934 561 13528 1.76 1.7E‐03GOTERM_BP_FAT negative regulation of biosynthetic process 69 6 6.7E‐06 934 573 13528 1.74 1.6E‐03GOTERM_BP_FAT negative regulation of macromolecule metabolic process 82 7 1.4E‐05 934 734 13528 1.62 2.8E‐03

GOTERM_BP_FAT negative regulation of nucleobase, nucleoside, nucleotide and nucleic acid metabolic process 60 5 6.4E‐05 934 512 13528 1.70 9.0E‐03

GOTERM_BP_FAT negative regulation of RNA metabolic process 46 4 8.3E‐05 934 362 13528 1.84 1.1E‐02

GOTERM_BP_FAT negative regulation of nitrogen compound metabolic pro‐cess 60 5 9.3E‐05 934 519 13528 1.67 1.2E‐02

GOTERM_BP_FAT negative regulation of transcription, DNA‐dependent 45 4 1.1E‐04 934 356 13528 1.83 1.4E‐02GOTERM_MF_FAT transcription repressor activity 42 3 1.2E‐04 921 316 12983 1.87 1.3E‐02

GOTERM_BP_FAT negative regulation of transcription from RNA polymerase II promoter 33 3 1.5E‐03 934 266 13528 1.80 9.0E‐02


46


miR‐9‐5p Annotation clusters Term Count % P‐value

List Total

Pop Hits

Pop Total FE

Benja‐mini

Annotation Cluster 7 Enrichment Score: 4.68 GOTERM_MF_FAT cytoskeletal protein binding 66 5 1.6E‐06 921 504 12983 1.85 7.9E‐04SP_PIR_KEYWORDS actin‐binding 34 3 4.8E‐05 1231 247 19235 2.15 1.2E‐03GOTERM_MF_FAT actin binding 43 4 1.2E‐04 921 326 12983 1.86 1.4E‐02 Annotation Cluster 8 Enrichment Score: 4.266 GOTERM_CC_FAT cytoplasmic vesicle 72 6 5.5E‐06 829 642 12782 1.73 3.8E‐04GOTERM_CC_FAT vesicle 74 6 6.9E‐06 829 670 12782 1.70 4.1E‐04SP_PIR_KEYWORDS cytoplasmic vesicle 34 3 2.2E‐05 1231 238 19235 2.23 6.9E‐04GOTERM_CC_FAT coated vesicle 25 2 8.7E‐05 829 159 12782 2.42 2.8E‐03GOTERM_CC_FAT clathrin‐coated vesicle 22 2 1.1E‐04 829 132 12782 2.57 3.3E‐03GOTERM_CC_FAT membrane‐bounded vesicle 59 5 3.5E‐04 829 568 12782 1.60 8.9E‐03GOTERM_CC_FAT cytoplasmic membrane‐bounded vesicle 57 5 4.8E‐04 829 550 12782 1.60 1.1E‐02 Annotation Cluster 9 Enrichment Score: 4.11 UP_SEQ_FEATURE zinc finger region:PHD‐type 14 1 1.8E‐05 1229 52 19113 4.19 6.1E‐03INTERPRO Zinc finger, PHD‐type, conserved site 19 2 4.3E‐05 1126 93 16659 3.02 5.9E‐02INTERPRO Zinc finger, PHD‐finger 18 2 4.5E‐05 1126 85 16659 3.13 3.1E‐02INTERPRO Zinc finger, PHD‐type 18 2 9.5E‐05 1126 90 16659 2.96 2.7E‐02SMART PHD 18 2 8.6E‐04 743 90 9079 2.44 2.3E‐01 Annotation Cluster 10 Enrichment Score: 3.93 GOTERM_BP_FAT cell projection organization 51 4 2.9E‐06 934 368 13528 2.01 1.3E‐03GOTERM_BP_FAT cell morphogenesis 49 4 5.6E‐06 934 356 13528 1.99 1.6E‐03GOTERM_BP_FAT cellular component morphogenesis 52 4 1.2E‐05 934 397 13528 1.90 2.4E‐03GOTERM_BP_FAT neuron differentiation 54 4 4.2E‐05 934 438 13528 1.79 6.8E‐03GOTERM_BP_FAT neuron projection morphogenesis 31 3 1.4E‐04 934 213 13528 2.11 1.7E‐02GOTERM_BP_FAT neuron development 43 4 1.5E‐04 934 339 13528 1.84 1.7E‐02GOTERM_BP_FAT cell projection morphogenesis 34 3 1.6E‐04 934 245 13528 2.01 1.8E‐02GOTERM_BP_FAT neuron projection development 35 3 1.7E‐04 934 256 13528 1.98 1.8E‐02GOTERM_BP_FAT cell morphogenesis involved in neuron differentiation 30 2 2.4E‐04 934 209 13528 2.08 2.5E‐02GOTERM_BP_FAT cell morphogenesis involved in differentiation 33 3 3.3E‐04 934 244 13528 1.96 3.1E‐02GOTERM_BP_FAT axonogenesis 28 2 3.4E‐04 934 193 13528 2.10 3.1E‐02GOTERM_BP_FAT cell part morphogenesis 34 3 3.7E‐04 934 256 13528 1.92 3.3E‐02GOTERM_BP_FAT axon guidance 15 1 1.5E‐02 934 107 13528 2.03 3.2E‐01


47


eTable 14: Functional annotation of genes regulated by miR-9-5p – transcrip-tion factors. The following table contains a DAVID analysis showing enrichment of transcription factor regulation for genes targeted by miR-9-5p. Only the hundred most significant transcription factors are shown. “FE” is fold enrichment. The list of all genes in the categories can be obtained from the authors by request.

miR‐9‐5p DAVID Transcription Factor regulation Count % P‐value List Total

Pop Hits

Pop Total FE

Benja‐mini

MEF2 1041 84 1.9E‐62 1229 12495 19536 1.3 3.5E‐60RSRFC4 762 62 8.9E‐62 1229 7682 19536 1.6 7.9E‐60FREAC3 713 58 2.1E‐61 1229 6955 19536 1.6 1.2E‐59HNF1 854 69 2.3E‐61 1229 9163 19536 1.5 1.0E‐59CART1 763 62 3.9E‐60 1229 7757 19536 1.6 1.4E‐58NKX25 932 76 1.8E‐59 1229 10569 19536 1.4 5.2E‐58FOXJ2 950 77 2.3E‐58 1229 10934 19536 1.4 5.7E‐57NKX22 725 59 4.4E‐58 1229 7253 19536 1.6 9.9E‐57TATA 828 67 8.6E‐58 1229 8874 19536 1.5 1.7E‐56FOXO1 688 56 1.7E‐57 1229 6724 19536 1.6 3.0E‐56FOXO4 830 67 2.6E‐57 1229 8925 19536 1.5 4.2E‐56HFH3 679 55 6.4E‐57 1229 6613 19536 1.6 9.4E‐56POU3F2 880 71 7.4E‐57 1229 9773 19536 1.4 1.0E‐55TBP 615 50 1.9E‐56 1229 5716 19536 1.7 2.4E‐55SOX5 760 62 3.3E‐56 1229 7857 19536 1.5 4.0E‐55CDP 888 72 7.8E‐56 1229 9950 19536 1.4 8.7E‐55E4BP4 704 57 8.9E‐55 1229 7060 19536 1.6 9.4E‐54CDC5 718 58 3.9E‐54 1229 7294 19536 1.6 3.9E‐53HFH1 720 58 1.2E‐53 1229 7342 19536 1.6 1.1E‐52FREAC7 758 61 2.0E‐53 1229 7933 19536 1.5 1.8E‐52EVI1 1086 88 1.1E‐51 1229 13849 19536 1.2 9.7E‐51SRY 679 55 2.5E‐51 1229 6819 19536 1.6 2.0E‐50PAX6 814 66 7.3E‐51 1229 8924 19536 1.4 5.6E‐50OCT1 1141 92 3.4E‐49 1229 15177 19536 1.2 2.5E‐48S8 715 58 4.6E‐49 1229 7446 19536 1.5 3.2E‐48CREBP1 732 59 1.2E‐48 1229 7723 19536 1.5 8.4E‐48FREAC4 718 58 1.8E‐48 1229 7516 19536 1.5 1.2E‐47HNF3B 657 53 3.0E‐47 1229 6653 19536 1.6 1.9E‐46OCT 716 58 8.6E‐47 1229 7554 19536 1.5 5.3E‐46MRF2 764 62 3.9E‐46 1229 8325 19536 1.5 2.3E‐45NKX3A 715 58 7.6E‐46 1229 7578 19536 1.5 4.3E‐45RORA2 724 59 2.1E‐45 1229 7734 19536 1.5 1.1E‐44POU6F1 669 54 7.1E‐45 1229 6926 19536 1.5 3.8E‐44FOXD3 570 46 1.1E‐44 1229 5509 19536 1.6 5.9E‐44HLF 643 52 2.1E‐44 1229 6562 19536 1.6 1.1E‐43SRF 965 78 3.9E‐44 1229 11813 19536 1.3 1.9E‐43PAX4 1035 84 7.2E‐44 1229 13147 19536 1.3 3.5E‐43CHX10 658 53 1.5E‐43 1229 6818 19536 1.5 7.1E‐43PBX1 828 67 1.5E‐43 1229 9470 19536 1.4 7.0E‐43CEBPB 805 65 3.8E‐43 1229 9112 19536 1.4 1.7E‐42CDPCR3 797 65 4.5E‐43 1229 8986 19536 1.4 2.0E‐42FOXO3 486 39 5.2E‐43 1229 4429 19536 1.7 2.2E‐42CEBP 1020 83 6.5E‐42 1229 12945 19536 1.3 2.7E‐41BRN2 745 60 8.8E‐42 1229 8218 19536 1.4 3.6E‐41AP1 848 69 2.6E‐40 1229 9952 19536 1.4 1.0E‐39MEIS1BHOXA9 743 60 3.1E‐40 1229 8257 19536 1.4 1.2E‐39IRF2 635 51 1.0E‐39 1229 6641 19536 1.5 3.8E‐39GATA1 1054 85 1.0E‐39 1229 13713 19536 1.2 3.8E‐39NFAT 642 52 1.1E‐39 1229 6746 19536 1.5 4.0E‐39FREAC2 535 43 1.4E‐39 1229 5220 19536 1.6 5.0E‐39SOX9 672 54 3.1E‐39 1229 7213 19536 1.5 1.1E‐38LHX3 588 48 4.6E‐39 1229 5987 19536 1.6 1.6E‐38NKX61 660 53 1.9E‐38 1229 7068 19536 1.5 6.3E‐38AML1 1015 82 3.9E‐37 1229 13077 19536 1.2 1.3E‐36GATA 668 54 3.1E‐36 1229 7290 19536 1.5 1.0E‐35


48


miR‐9‐5p DAVID Transcription Factor regulation Count % P‐value List Total

Pop Hits

Pop Total FE

Benja‐mini

EN1 765 62 5.9E‐36 1229 8809 19536 1.4 1.9E‐35ISRE 658 53 9.8E‐36 1229 7163 19536 1.5 3.1E‐35LMO2COM 820 66 4.1E‐35 1229 9743 19536 1.3 1.3E‐34YY1 935 76 7.3E‐35 1229 11722 19536 1.3 2.2E‐34IRF7 668 54 1.3E‐34 1229 7368 19536 1.4 4.0E‐34FAC1 695 56 4.5E‐34 1229 7806 19536 1.4 1.3E‐33PAX2 810 66 5.3E‐33 1229 9688 19536 1.3 1.5E‐32HTF 756 61 6.0E‐33 1229 8818 19536 1.4 1.7E‐32BRACH 771 62 3.7E‐32 1229 9099 19536 1.3 1.0E‐31MYB 661 54 4.4E‐32 1229 7386 19536 1.4 1.2E‐31BACH1 716 58 5.2E‐32 1229 8236 19536 1.4 1.4E‐31STAT 546 44 7.6E‐32 1229 5705 19536 1.5 2.0E‐31MSX1 619 50 9.3E‐32 1229 6772 19536 1.5 2.4E‐31MZF1 696 56 1.1E‐31 1229 7943 19536 1.4 3.0E‐31CHOP 691 56 1.7E‐31 1229 7875 19536 1.4 4.4E‐31E2F 788 64 1.8E‐31 1229 9411 19536 1.3 4.6E‐31NFY 696 56 2.8E‐31 1229 7963 19536 1.4 6.9E‐31IK3 648 53 5.8E‐31 1229 7246 19536 1.4 1.4E‐30TCF11MAFG 738 60 9.0E‐31 1229 8647 19536 1.4 2.2E‐30MYCMAX 846 69 1.2E‐30 1229 10413 19536 1.3 2.9E‐30HOXA3 611 50 2.4E‐30 1229 6724 19536 1.4 5.7E‐30SREBP1 821 67 2.5E‐30 1229 10014 19536 1.3 5.9E‐30HAND1E47 668 54 2.7E‐30 1229 7584 19536 1.4 6.1E‐30RORA1 648 53 4.2E‐30 1229 7290 19536 1.4 9.4E‐30IRF1 420 34 9.6E‐30 1229 4059 19536 1.6 2.1E‐29CDPCR1 582 47 1.0E‐29 1229 6328 19536 1.5 2.3E‐29BACH2 630 51 1.1E‐29 1229 7041 19536 1.4 2.4E‐29STAT1 589 48 1.7E‐29 1229 6442 19536 1.5 3.7E‐29CEBPA 459 37 1.9E‐29 1229 4598 19536 1.6 3.9E‐29PPARG 1037 84 2.5E‐29 1229 13898 19536 1.2 5.1E‐29TGIF 618 50 3.2E‐29 1229 6885 19536 1.4 6.5E‐29GFI1 641 52 6.3E‐29 1229 7246 19536 1.4 1.3E‐28AREB6 1060 86 1.2E‐28 1229 14383 19536 1.2 2.5E‐28RFX1 826 67 3.7E‐28 1229 10219 19536 1.3 7.4E‐28NFE2 535 43 6.9E‐28 1229 5738 19536 1.5 1.4E‐27GRE 671 54 7.0E‐28 1229 7760 19536 1.4 1.4E‐27GCNF 778 63 1.0E‐27 1229 9457 19536 1.3 2.0E‐27P53 869 70 1.7E‐27 1229 10980 19536 1.3 3.3E‐27CDPCR3HD 638 52 3.8E‐27 1229 7297 19536 1.4 7.2E‐27TCF11 703 57 1.2E‐26 1229 8326 19536 1.3 2.3E‐26TST1 629 51 1.2E‐26 1229 7189 19536 1.4 2.3E‐26RP58 717 58 2.4E‐26 1229 8563 19536 1.3 4.5E‐26USF 786 64 2.4E‐25 1229 9727 19536 1.3 4.3E‐25MEIS1AHOXA9 519 42 2.4E‐25 1229 5638 19536 1.5 4.3E‐25STAT5B 497 40 2.6E‐25 1229 5326 19536 1.5 4.7E‐25


49


eTable 15: Genes in the schizophrenia enriched miR-9-5p subset. This subset of 497 co-expressed gene targets of the miR-9-5p targetome was found enriched in schizophrenia genes. Genes located in GWAS regions (clumps) with p-values < 1 x 10-5 in PGC2 are underlined and additionally printed in bold if the p-value was < 5 x 10-8 in PGC2. Note that these p-values are taking the PGC2 replication into account. Subset of the miR‐9‐5‐p targetome (497 genes)

ABAT, ABCA1, ABL2, ACTR1A, ACVR1B, ADAM10, ADCY6, ADPGK, AEBP2, AFAP1, AGFG1, AHDC1, AK2, AKAP11, ALAD, ALG6, ALG9, AMBRA1, AMER1, AMOTL1, AMOTL2, ANK2, ANKRD12, ANKRD13A, ANKRD40, ANP32B, AP2M1, AP3B1, AP4E1, ARCN1, ARF6, ARFIP2, ARHGAP39, ARHGDIA, ARHGEF2, ARID1A, ASB7, ASPH, ASXL1, ATF1, ATG14, ATP11A, ATP11B, ATP11C, ATP7A, ATP8A1, ATXN3, BAHD1, BAIAP2, BCLAF1, BRAF, BRD4, BTBD7, C11orf58, C17orf70, C17orf85, C18orf25, C19orf55, C21orf91, C4orf46, C5orf24, C7orf25, CAMKK2, CAP1, CAPZA1, CARM1, CBFA2T2, CBL, CBX5, CCDC43, CCDC50, CCDC88A, CCNDBP1, CCNG1, CCNJ, CCNT2, CCSER2, CD46, CD47, CDC23, CDC73, CEP350, CEP63, CERS2, CERS6, CHD3, CHSY1, CISD3, CLIC4, CMTM6, CMTR2, CNNM4, CNOT6L, CNP, COG3, COG6, CPSF6, CREBRF, CREBZF, CTDP1, CTDSP2, CTNNA1, CUL4A, CXCR4, DBNL, DBT, DCAF10, DCBLD2, DCP2, DDX17, DEDD, DEDD2, DGCR8, DHX40, DIAPH1, DICER1, DNAJB1, DNAJC14, DNAJC3, DNAJC8, DOLPP1, DONSON, DOT1L, DSE, DTD1, DYNC1LI2, DYRK1B, DYRK2, ECHDC1, ELAVL1, ELAVL2, ELL, ELMOD2, ENAH, ENTPD1, ENTPD5, ENTPD7, EP400, EPHB2, ERBB2IP, ERP44, EXTL3, FAF2, FAM107B, FAM115A, FAM117B, FAM118A, FAM155B, FAM19A5, FAM58A, FAM63B, FARP1, FBXL19, FBXO28, FBXO33, FMR1, FNDC3B, FOXN2, FOXN3, FOXO3, FRMD4A, FRY, FXR1, FYTTD1, GALNT4, GDF11, GFPT1, GIGYF1, GLCCI1, GLG1, GLTSCR1L, GMEB2, GNA13, GNPNAT1, GOLPH3, GOPC, GOSR1, GPATCH8, GPBP1L1, GPR153, GRSF1, GTPBP1, GTPBP3, GXYLT1, GZF1, HCFC2, HDAC4, HDAC5, HIAT1, HIPK1, HLCS, HMG20A, HN1L, HOOK3, HSP90AA1, HUNK, ICMT, ID4, IGF2R, IKZF4, INSIG1, IPO11, IPO13, IPO4, ITM2C, ITPKC, JHDM1D, JMY, JUP, KCNK10, KCTD10, KCTD12, KDM5A, KIAA0754, KIAA0930, KIAA1549, KIAA1549L, KIAA1967, KIAA2013, KLF12, KLF13, KLHDC10, KLHL24, KPNB1, LAMP1, LASP1, LDLRAD3, LGALSL, LHFP, LIFR, LIN7C, LMAN1, LSM14A, MAEA, MAGI1, MAP3K1, MAP3K3, MAPKAPK2, MARCH6, MBTPS1, MCMBP, MESDC1, MGA, MGAT1, MICAL3, MICALL1, MIER3, MKLN1, MKRN2, MLXIP, MMP15, MMP16, MNT, MPP3, MRE11A, MRFAP1, MTF2, MTHFD1L, MTHFD2, MTR, MYO1D, NAP1L1, NCOA3, NCOR2, NEK1, NEO1, NFATC3, NHP2L1, NLN, NMT2, NPLOC4, NRF1, NTAN1, NUS1, NUTF2, NXPE3, OSBPL11, OTUD3, OXSR1, PAK2, PANK3, PBRM1, PCGF6, PCNX, PDCD6IP, PDE3B, PEG3, PGAP1, PGRMC2, PHACTR4, PHF13, PHF20L1, PHF21A, PHF8, PHTF2, PIGM, PIK3C2A, PIK3R3, PIM3, PLSCR3, PLXNA2, POC1B‐GALNT4, POU2F1, PPAPDC2, PPAT, PPIP5K2, PPM1F, PPP2R4, PPP2R5D, PPP6R3, PRDM10, PRKCA, PRKD3, PRUNE, PSMD9, PTAR1, PTBP1, PTBP2, PTBP3, PTCH1, PTGFRN, PTMA, PUS10, PYGO2, RAB33B, RAB8A, RABGEF1, RALGAPB, RALGDS, RANBP17, RAP1B, RAP2C, RAPH1, RBFOX2, RC3H1, RCOR1, RERE, RFX1, RFX7, RMND5A, RNF111, RNF144A, RNF169, RNF19A, RNF24, RNF38, RP2, RPS6KA6, RTF1, S100PBP, S1PR3, SACM1L, SACS, SAP30L, SAR1B, SASS6, SCUBE3, SCYL3, SEC23IP, SEMA6D, SENP1, SEPT10, SFMBT1, SH3BP4, SH3GLB1, SH3PXD2B, SHC3, SHISA5, SHISA6, SHROOM3, SIN3A, SIRT1, SLAIN2, SLC19A2, SLC20A2, SLC22A23, SLC25A24, SLC25A36, SLC26A2, SLC30A5, SLC33A1, SLC35B3, SLC39A9, SLC5A3, SMAD4, SMAP2, SMARCA5, SMARCE1, SMC1A, SMEK1, SMPD4, SMURF1, SNIP1, SNX25, SNX30, SOAT1, SOCS4, SON, SPAG9, SPECC1L, SPG20, SPRYD4, SPTSSA, SRC, SRCAP, SREK1IP1, SRF, SRRM4, SRSF1, SRSF10, SRSF6, ST3GAL2, ST8SIA4, STXBP1, SUPT7L, SYNJ2BP, SYT1, SZRD1, SZT2, TAB3, TBC1D2B, TBC1D4, TEAD1, TES, TFRC, TGFBR1, THAP2, THOC5, TMEM110, TMEM136, TMEM164, TNKS, TNRC6B, TOX4, TRA2B, TRAM1, TRERF1, TRIM11, TRIM9, TRPM7, TSC22D2, TSPAN18, TSPAN9, TUFT1, TULP4, TXNDC5, UBASH3B, UBE2H, UBE2Q1, UBE3A, UBE4B, UBN2, UBR5, UBXN7, UHRF1BP1, UPF3B, USP31, VAT1, VCAN, VGLL4, WAPAL, WASF2, WDTC1, WIPI2, WIZ, WWP2, XPO4, XRN1, XYLT1, ZBED3, ZBTB1, ZBTB14, ZBTB34, ZBTB39, ZBTB44, ZC3H10, ZDHHC18, ZDHHC20, ZDHHC5, ZFP90, ZKSCAN1, ZNF131, ZNF236, ZNF24, ZNF248, ZNF280D, ZNF319, ZNF354A, ZNF362, ZNF395, ZNF407, ZNF48, ZNF512, ZNF629, ZNF646, ZNF704, ZNRF2


50


eTable 16: Gene set results for miRNA in schizophrenia GWAS loci. The gene set analysis for the targets of miRNA located in genome-wide significant schizophrenia GWAS loci was performed using three different prediction methods. The number of miRNA varies between the prediction methods as not all miRNA have predictions for each method. The three different thresholds represent the differ-ent significance thresholds for the index-SNP used in clumping. Top-1% of SNPs have p-values less than 3.420 x 10-4, top 5% of SNPs have p-values less than 1.096 x 10-2. “Size” indicates the number of genes in the gene set. “Brain” indicates the percentage of the test genes expressed in the brain. “Corrected” are the p-values after cor-recting for multiple testing, whereas “Raw” are the unadjusted p-values. For a detailed description of the “Score” column please refer to the main text.

miRNA in GWAS Loci (R2=0.6, 500kb)

p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

TargetScan

miR‐4677‐3p 2.2E‐02 4.7E‐01 2.2E‐04 80 3333 69% 1.3E‐03 4.0E‐02 1.3E‐06

miR‐33a‐5p 1.1E‐01 6.0E‐02 5.5E‐03 75 2832 68% 7.5E‐03 3.4E‐03 2.8E‐04

miR‐3160‐3p 3.6E‐01 1.6E‐01 2.2E‐04 54 3343 69% 2.8E‐02 9.7E‐03 1.3E‐06

miR‐4688 8.1E‐02 6.9E‐01 2.2E‐04 46 2842 71% 5.1E‐03 7.7E‐02 1.3E‐06

miR‐137 1.5E‐01 8.1E‐01 2.2E‐04 33 2742 69% 9.8E‐03 1.1E‐01 1.3E‐06

miR‐3160‐5p 1.9E‐01 9.3E‐01 2.2E‐04 27 3496 68% 1.3E‐02 1.9E‐01 1.3E‐06

miR‐1281 8.9E‐01 2.3E‐01 9.4E‐04 22 1174 70% 1.5E‐01 1.5E‐02 4.5E‐05

miR‐4529‐5p 9.6E‐01 3.0E‐01 2.2E‐04 22 2181 70% 2.1E‐01 2.2E‐02 1.3E‐06

miR‐4677‐5p 6.5E‐01 8.5E‐01 2.5E‐04 16 3521 68% 6.8E‐02 1.3E‐01 5.0E‐06

miR‐640 9.7E‐01 4.9E‐01 4.1E‐04 16 2081 67% 2.4E‐01 4.4E‐02 1.5E‐05

miR‐1228‐3p 8.6E‐01 8.4E‐01 2.2E‐04 13 3029 71% 1.4E‐01 1.2E‐01 1.3E‐06

miR‐2682‐5p 1.0E+00 4.0E‐01 6.4E‐03 12 2023 69% 4.1E‐01 3.1E‐02 3.3E‐04

miR‐4301 9.3E‐01 9.5E‐01 2.2E‐04 11 2473 66% 1.9E‐01 2.1E‐01 1.3E‐06

miR‐4655‐3p 9.6E‐01 9.9E‐01 1.3E‐03 8 652 69% 2.2E‐01 3.6E‐01 6.1E‐05

miR‐130a‐3p 8.0E‐01 4.3E‐01 1.2E‐01 7 932 70% 1.1E‐01 3.5E‐02 6.9E‐03

miR‐1307‐3p 1.0E+00 9.2E‐01 4.6E‐02 4 987 66% 6.0E‐01 1.7E‐01 2.5E‐03

miR‐4529‐3p 1.0E+00 1.0E+00 3.8E‐02 4 1807 70% 4.9E‐01 7.2E‐01 2.0E‐03

miR‐29b‐3p 8.8E‐01 8.9E‐01 1.1E‐01 4 444 66% 1.5E‐01 1.5E‐01 6.4E‐03

miR‐4655‐5p 1.0E+00 8.9E‐01 2.2E‐01 3 488 72% 4.1E‐01 1.5E‐01 1.5E‐02

miR‐4304 7.4E‐01 9.9E‐01 9.8E‐01 1 490 72% 8.8E‐02 3.6E‐01 2.9E‐01

miR‐3655 1.0E+00 1.0E+00 7.7E‐01 1 1470 67% 4.1E‐01 6.5E‐01 1.0E‐01

miR‐33b‐5p 1.0E+00 1.0E+00 9.1E‐01 1 65 75% 1.0E+00 9.3E‐01 1.8E‐01

miR‐378i NA NA NA 1 13 88% NA NA NA

miR‐29c‐3p NA NA NA 1 1 100% NA NA NA

MiRanda

miR‐640 5.3E‐01 4.6E‐01 5.4E‐03 18 1869 71% 5.5E‐02 4.4E‐02 3.3E‐04

miR‐130a‐3p 7.0E‐01 9.2E‐01 1.6E‐04 14 2957 72% 8.6E‐02 1.8E‐01 2.5E‐06

miR‐33b‐3p 9.2E‐01 8.9E‐01 1.5E‐04 12 1780 70% 1.9E‐01 1.6E‐01 1.3E‐06

miR‐3160‐3p 1.0E+00 9.1E‐01 1.5E‐04 11 2726 70% 7.5E‐01 1.8E‐01 1.3E‐06

miR‐130a‐5p 9.4E‐01 1.0E+00 1.5E‐04 10 4469 70% 2.2E‐01 6.0E‐01 1.3E‐06

miR‐33a‐3p 1.0E+00 1.0E+00 1.5E‐04 10 5293 70% 8.6E‐01 6.8E‐01 1.3E‐06

miR‐1228‐3p 1.0E+00 9.9E‐01 1.6E‐04 10 1967 73% 5.5E‐01 3.7E‐01 2.5E‐06

miR‐137 9.9E‐01 9.5E‐01 2.8E‐04 10 3050 71% 3.2E‐01 2.2E‐01 1.3E‐05

miR‐29c‐3p 1.0E+00 1.0E+00 1.6E‐04 10 2534 72% 6.7E‐01 6.1E‐01 2.5E‐06

miR‐29b‐3p 1.0E+00 1.0E+00 1.6E‐04 10 2762 72% 7.0E‐01 7.3E‐01 3.8E‐06

miR‐29b‐2‐5p 1.0E+00 9.7E‐01 4.1E‐04 9 3636 70% 5.0E‐01 2.5E‐01 2.0E‐05

miR‐4301 4.0E‐01 3.9E‐01 2.6E‐01 9 1272 67% 3.5E‐02 3.5E‐02 2.1E‐02

miR‐33a‐5p 8.2E‐01 1.0E+00 1.4E‐01 4 2801 70% 1.3E‐01 5.9E‐01 1.0E‐02

miR‐29c‐5p 1.0E+00 9.8E‐01 1.4E‐01 3 318 68% 5.7E‐01 2.8E‐01 1.0E‐02

miR‐4304 1.0E+00 1.0E+00 1.6E‐01 3 532 75% 6.0E‐01 3.9E‐01 1.2E‐02

miR‐1228‐5p 1.0E+00 1.0E+00 1.8E‐01 3 517 72% 6.0E‐01 7.2E‐01 1.4E‐02

miR‐33b‐5p 1.0E+00 1.0E+00 3.4E‐01 2 2647 71% 3.8E‐01 5.9E‐01 3.0E‐02

miR‐1281 1.0E+00 6.6E‐01 8.6E‐01 2 639 74% 6.1E‐01 7.9E‐02 1.6E‐01

miR‐1307‐3p 1.0E+00 1.0E+00 9.6E‐01 1 196 73% 8.3E‐01 8.5E‐01 2.5E‐01


51


miRNA in GWAS Loci (R2=0.6, 500kb)

p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

TargetMiner

miR‐1228‐5p 3.7E‐01 1.4E‐03 2.3E‐04 141 2115 77% 3.4E‐02 6.5E‐05 2.5E‐06

miR‐4688 1.2E‐01 4.5E‐02 2.3E‐04 121 3775 77% 8.2E‐03 2.6E‐03 1.3E‐06

miR‐2682‐5p 4.1E‐02 2.6E‐01 2.3E‐04 92 4602 76% 2.5E‐03 1.9E‐02 1.3E‐06

miR‐3160‐3p 4.7E‐02 7.9E‐02 7.4E‐02 52 3536 77% 2.8E‐03 4.6E‐03 4.3E‐03

miR‐130a‐3p 4.6E‐01 1.1E‐01 3.4E‐02 25 3853 77% 4.6E‐02 6.8E‐03 1.9E‐03

miR‐33b‐3p 2.9E‐01 4.7E‐01 8.4E‐03 23 1784 76% 2.5E‐02 4.5E‐02 4.3E‐04

miR‐1281 1.0E+00 1.8E‐01 1.7E‐03 20 717 79% 8.1E‐01 1.3E‐02 8.1E‐05

miR‐4655‐5p 9.3E‐01 3.5E‐01 4.4E‐02 9 348 74% 2.3E‐01 2.8E‐02 2.5E‐03

miR‐29b‐2‐5p 9.7E‐01 6.1E‐02 4.7E‐01 7 1525 75% 3.1E‐01 3.7E‐03 4.7E‐02

miR‐4677‐3p 2.0E‐01 2.4E‐01 9.8E‐01 6 2353 75% 1.5E‐02 1.8E‐02 3.4E‐01

miR‐4304 7.4E‐01 4.3E‐01 2.4E‐01 6 2401 76% 1.1E‐01 3.9E‐02 1.8E‐02

miR‐4677‐5p 4.2E‐01 1.4E‐01 9.9E‐01 6 745 72% 4.1E‐02 9.3E‐03 3.9E‐01

miR‐137 7.7E‐01 4.0E‐02 9.8E‐01 5 713 74% 1.3E‐01 2.2E‐03 3.7E‐01

miR‐1307‐3p 9.4E‐01 7.1E‐01 1.2E‐01 4 790 78% 2.5E‐01 9.7E‐02 7.5E‐03

miR‐33ab‐5p 7.3E‐01 2.1E‐01 9.9E‐01 3 2339 76% 1.1E‐01 1.5E‐02 4.4E‐01

miR‐29bc‐3p 9.6E‐01 9.2E‐01 1.6E‐01 3 1767 77% 2.8E‐01 2.2E‐01 1.1E‐02

miR‐3160‐5p 7.5E‐01 4.2E‐01 9.8E‐01 2 804 74% 1.2E‐01 3.7E‐02 3.4E‐01

miR‐33a‐3p 5.4E‐01 6.4E‐01 9.6E‐01 2 1837 74% 6.0E‐02 8.1E‐02 2.8E‐01

miR‐4529‐5p 9.6E‐01 6.2E‐01 5.8E‐01 2 1205 76% 3.0E‐01 7.5E‐02 6.5E‐02

miR‐378i 6.6E‐01 5.5E‐01 9.7E‐01 2 158 76% 8.4E‐02 6.0E‐02 3.1E‐01

miR‐130a‐5p 1.0E+00 6.6E‐01 1.0E+00 1 145 73% 7.3E‐01 8.4E‐02 7.5E‐01

miR‐2682‐3p 9.8E‐01 9.1E‐01 8.0E‐01 1 355 79% 3.5E‐01 2.1E‐01 1.4E‐01

miR‐4529‐3p 1.0E+00 8.2E‐01 9.8E‐01 1 213 75% 4.9E‐01 1.4E‐01 3.5E‐01

miR‐3655 1.0E+00 1.0E+00 1.0E+00 1 74 76% 6.3E‐01 7.0E‐01 9.5E‐01




miR‐29c‐5p NA NA NA 1 15 60% NA NA NA




52


eTable 17: Gene set results for miRNA in schizophrenia CNVs. The gene set analysis for the targets of miRNA located in schizophrenia associated CNVs was performed using three different prediction methods. The number of miRNA varies between the prediction methods as not all miRNA have predictions for each method. The three different thresholds represent the different significance thresholds for the index-SNP used in clumping. Top-1% of SNPs have p-values less than 3.420 x 10-4, top 5% of SNPs have p-values less than 1.096 x 10-2. “Size” indicates the number of genes in the gene set. “Size” indicates the number of genes in the gene set. “Brain” indicates the percentage of the test genes expressed in the brain. “Corrected” are the p-values after correcting for multiple testing, whereas “Raw” are the unadjusted p-values. For a detailed description of the “Score” column please refer to the main text.

miRNA in CNVs (R2=0.6, 500kb)

p‐value @1E‐5


p‐value @top5%

Score

Size

Brain

p‐value @1E‐5


p‐value @top5%

TargetScan

miR‐922 1.0E‐01 1.1E‐02 1.2E‐04 183 4226 69% 1.3E‐02 1.3E‐03 1.3E‐06

miR‐185‐5p 1.1E‐02 1.4E‐01 1.2E‐04 165 2484 69% 1.4E‐03 1.8E‐02 1.3E‐06

miR‐4761‐5p 3.7E‐01 3.3E‐01 3.8E‐03 28 2853 68% 5.8E‐02 5.1E‐02 4.0E‐04

miR‐3680‐5p 3.6E‐01 9.7E‐01 1.9E‐02 10 1989 69% 5.8E‐02 4.3E‐01 2.1E‐03

miR‐4761‐3p 9.3E‐01 1.0E+00 1.0E‐03 8 2272 68% 3.2E‐01 8.8E‐01 9.9E‐05

miR‐4509 9.9E‐01 7.8E‐01 3.8E‐03 8 2738 69% 4.9E‐01 2.0E‐01 4.0E‐04

miR‐1306‐3p 9.9E‐01 5.2E‐01 8.7E‐02 6 404 69% 4.9E‐01 9.0E‐02 1.1E‐02

miR‐648 9.3E‐01 1.0E+00 4.1E‐02 5 1904 70% 3.2E‐01 8.5E‐01 4.7E‐03

miR‐3618 9.5E‐01 9.3E‐01 2.6E‐01 3 1728 68% 3.7E‐01 3.3E‐01 3.8E‐02

miR‐3198 8.7E‐01 8.9E‐01 8.6E‐01 1 1453 68% 2.6E‐01 2.8E‐01 2.7E‐01

MiRanda

miR‐185‐3p 5.0E‐01 6.2E‐01 5.0E‐05 27 2493 72% 1.3E‐01 1.7E‐01 1.3E‐06

miR‐185‐5p 9.4E‐01 7.6E‐01 4.7E‐04 12 3365 70% 4.4E‐01 2.5E‐01 9.5E‐05

miR‐648 7.2E‐02 3.1E‐01 6.7E‐01 11 1660 72% 1.4E‐02 7.2E‐02 2.0E‐01

miR‐922 8.8E‐01 7.7E‐01 2.6E‐03 10 3778 71% 3.6E‐01 2.6E‐01 4.4E‐04

miR‐3198 9.0E‐01 9.9E‐01 1.7E‐01 3 2141 69% 3.8E‐01 6.6E‐01 3.4E‐02

miR‐1306‐3p 1.0E+00 7.4E‐01 9.8E‐01 1 522 71% 8.4E‐01 2.4E‐01 6.0E‐01

TargetMiner

miR‐185‐5p 6.8E‐03 8.7E‐05 1.6E‐04 604 4029 76% 7.8E‐04 2.5E‐06 7.5E‐06

miR‐4761‐3p 6.4E‐02 2.2E‐04 2.7E‐04 326 3926 77% 8.4E‐03 1.4E‐05 2.1E‐05

miR‐185‐3p 1.5E‐01 5.2E‐04 1.2E‐04 250 3353 76% 2.1E‐02 4.9E‐05 1.3E‐06

miR‐3198 1.9E‐03 5.1E‐03 1.6E‐02 234 3021 75% 2.0E‐04 6.2E‐04 1.8E‐03

miR‐4761‐5p 1.1E‐02 5.0E‐02 6.1E‐02 83 3877 76% 1.2E‐03 6.4E‐03 7.9E‐03

miR‐922 7.3E‐01 3.6E‐01 6.6E‐03 16 2379 78% 2.1E‐01 6.4E‐02 7.3E‐04

miR‐4509 1.7E‐01 9.6E‐02 6.3E‐01 13 3388 76% 2.7E‐02 1.3E‐02 1.6E‐01

miR‐648 7.5E‐01 2.1E‐02 6.7E‐01 9 1233 78% 2.2E‐01 2.6E‐03 1.8E‐01

miR‐1306‐3p 9.0E‐01 6.5E‐02 3.4E‐01 9 1148 77% 3.6E‐01 8.3E‐03 6.2E‐02

miR‐3680‐3p 9.9E‐01 5.9E‐01 8.9E‐01 2 2652 76% 6.2E‐01 1.4E‐01 3.6E‐01

miR‐3618 8.3E‐01 6.9E‐01 1.0E+00 2 87 75% 2.7E‐01 1.8E‐01 7.4E‐01




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