Carrie E. Bearden, Ph.D. Psychiatry and Biobehavioral Sciences and PsychologySemel Institute for Neuroscience and Human BehaviorUniversity of California, Los Angelescbearden@mednet.ucla.edu

Brain Development in 22q11.2 Deletion Syndrome

Convergence of genes on neural systems

Geschwind 2011

Schizophrenia

Key Questions

ØLimited data on individuals carrying the same highly penetrant CNV;What are the most robust/reproducible effects of a 22q11.2 deletion on the brain?

-cortical and subcortical structures

ØDo imaging biomarkers identified in idiopathic psychosis also predict psychotic symptoms in 22q11 DS?

ØInvestigation of genetically homogeneous, known etiology- may tell us how genes within and/or outside deleted region contribute to disrupted biological pathways that ultimately contribute to psychiatric phenotypes

ØPremise: Hemizygous deletion may have a more powerful effect on phenotypic variation than common genetic variation.

Gray Matter Thinning in anterior cingulate and medial frontal cortex in 22q11DS

Bearden et al. Cerebral Cortex 2009

Kana et al. Soc Neurosci 2009

Frontal “Theory of Mind” Network

http://enigma.ini.usc.edu/?p=4900

22q-ENIGMA Current Demographics

Brain Imaging Analysis: Cortical Thickness vs. Surface Area

• Driven by distinct genetic mechanisms1,2

• Different underlying neurobiology– Surface area is considered to

represent the number of cortical columns3

– Cortical thickness is a proxy for the number of cells in a column4

Methods

-All raw data processed via Freesurfer5.3.0 using ENIGMA processing pipeline -Covaried for age, sex, and scanner

1Winkler et al., 2009; 2Panizzon et al., 2009;3Rakic et al. 1988;4Pontius et al., 2008

• Volume measures are derived from indices of both cortical thickness and surface area

Most Significant Cortical Measures: 22q11DS Case vs. Control

Jonas et al 2014 (adapted from Tan et al 2009 meta-analysis)

Reduced SA Due to Reduced Gyrification in 22q11DS

Gyrification Index: Measure of cortical folding

Machine Learning Classification of 22q11DS Case-Control Status

• GLMNET algorithm (20 10-fold cross-validations)• Feature selection based on Random Forest algorithm

-Accuracy peaks at 94.44% (125 features)-Cuneus & lingual SA, and caudal anterior cingulate volume

among most important features for classification

Accuracy of 86.36% achieved using bilateral cuneus and lingual SA for classification

Sun et al, in prep

High Consistency of Brain Measures Across Sites

Prodromal/Psychotic (n=45) vs. Non-Psychotic (n=81): Greatest Effects for SA in Somatosensory, Heteromodal Association Regions

Sun et al, in prep

Greatest Effects for SA in Somatosensory, Heteromodal Association Regions: Overlap with Idopathic (non-22q) Psychosis

SCZ data courtesy of van Erp & Turner et al. in submission

Longitudinal Findings: Three-way (brain region x time x group) interactions associated with psychotic symptom change over time

Green et al Nat Rev Neurosci 2015

Brain Regions associated with Social Processes

22q11DS(n=184)vs.Controls(n=137)

• Red/Yellow=22q11DS>surfacearea/volumevs.Controls• Blue/Green=22q11DS<Controls

GlobusPallidus

CaudatePutamen

HippocampusHippocampus

Amygdala

ThalamusThalamus

PutamenNucleusAccumbens

Ching et al, in prep

Summary & Implications²Largest MRI sample to date of this CNV; Neuroanatomic patterns allow highly accurate classification of 22q11DS patients relative to controls.

²Reductions in heteromodal association cortex (particularly in SA) converge with regions affected in idiopathic schizophrenia

²Utility of high-penetrance models: 22q11DS may account for only small proportion of risk for psychotic illness overall, but dysregulated genes/pathways may contribute to broader psychosis susceptibility

²Translational investigation -mechanistic studies in animal and cellular models.

Neurobehavioral Genetics Giovanni CoppolaNelson Freimer

Roel OphoffDan Geschwind

USC Imaging Genetics CenterJulio VillalonJustin GalvisConor CorbinPaul Thompson

22q-ENIGMA Working GroupMaria Gudbrandsen, Eileen Daly,

Christine Ecker, Clodagh Murphy, Declan Murphy, Michael Craig, Geor Bakker,

Therese van Amelsvoort, Linda Campbell, Wendy R. Kates, Liz Gras, Ania Faskinski, Jacob Vorstman, Tony Simon, Eva Chow,

Nancy Butcher, Anne Bassett

22q11.2 International Brain Behavior Consortium (Raquel Gur, Thomas Lehner)

Lab MembersMaria Jalbrzikowski Matthew Schreiner

Rachel JonasLeila KushanCarolyn Chow

Amira IbrahimCaroline MontojoAriel SchvarczSteffie TomsonTherese VesagasChristopher Ching

Daqiang (Frank) SunJamie Zinberg

Katie YoungAmy Lin

Acknowledgements

This work supported by: the National Institute of Mental Health (NIMH), ENIGMA Center for Worldwide Medicine, Imaging &

Genomics ( NIH/NIBIB), the Staglin/IMHRO Music Festival, the Brain-Behavior Research Foundation (NARSAD), and all the

patients and their families who participated.