Genetics Core Update & Planning

ADNI-2 Steering Committee

PhiladelphiaApril 28, 2014

Andy SaykinIndiana University

asaykin@iupui.edu

ADNI Genetics Papers: 3 (2009) + 23 (2010) + 28 (2011) + 52 (2012) + 65 (2013) = 171

Shen et al, Brain Imaging Behav 2013; Yao et al, AAIC 2014

Publications using ADNI GWAS and APOE Data

Distribution of publications using the ADNI APOE and GWAS/WES genotyping data between 2009 and 2013: Of the 171 papers, 65 papers

used only APOE data, and 106 papers used GWAS data.

Updated APOE Genotyping ADNI-1/GO/2 (n=1720)

and Initial Analyses of the Role of APOE in the Significant Memory Concern

(SMC) Group

(5)

(n = 391) (n = 98) (n = 315) (n = 320) (n = 596)

(3) (5) (7) (14)

(92) (27) (99) (105) (279)

(105)

(10)

(1)

(21)

(34)

Total n’s:

Number of participants in parentheses Risacher et al (submitted)

April 2014, N=1720

Amyloid Deposition (Florbetapir PET): Diagnosis and APOE ε4 Influence

Overall: p<0.001DX: p=0.009

APOE: p<0.001Interaction: not sign.

Sign. Bonferroni Pairs (p<0.05):HC ε4+, SMC ε4+, EMCI ε4+ > HC ε4-

SMC ε4+, EMCI ε4+ > SMC ε4-, EMCI ε4-

Overall: p<0.001DX: p=0.006

APOE: p<0.001Interaction: not sign.

Sign. Bonferroni Pairs (p<0.05):HC ε4+, SMC ε4+, EMCI ε4+ > HC ε4-

SMC ε4+, EMCI ε4+ > SMC ε4-, EMCI ε4-

Risacher SL, Kim S, Nho K, West JD, Wang Y, Petersen RC, Aisen PS, Jack CR, Jagust WJ, Koeppe RA, Weiner MW, Saykin AJ. Increased amyloid deposition in older adults at risk for progression to Alzheimer’s disease due to genetic background and/or the presence of significant memory concerns. 2014 AAIC Oral Presentation, Wednesday, July 16 th; Session Title: Imaging in Mild Cognitive Impairment and Subjective Memory Complaint

Glucose Metabolism (FDG PET): Interaction of Diagnosis and APOE ε4 Status

Overall: p=0.013DX: not sign.

APOE: not sign.Interaction: p=0.030

Sign. Bonferroni Pairs (p<0.05):EMCI ε4- > EMCI ε4+

Overall: p=0.004DX: p=0.046

APOE: not sign.Interaction: p=0.017

Sign. Bonferroni Pairs (p<0.05):EMCI ε4- > EMCI ε4+

Trend Bonferroni Pairs (p<0.1):HC ε4-, SMC ε4-, SMC ε4+ > EMCI ε4+

Risacher SL, Kim S, Nho K, West JD, Wang Y, Petersen RC, Aisen PS, Jack CR, Jagust WJ, Koeppe RA, Weiner MW, Saykin AJ. Increased amyloid deposition in older adults at risk for progression to Alzheimer’s disease due to genetic background and/or the presence of significant memory concerns.

2014 AAIC Oral Presentation, Wednesday, July 16th; Session Title: Imaging in Mild Cognitive Impairment and Subjective Memory Complaint

Neurodegeneration (Hippocampus): Diagnosis vs APOE ε4 Status

Overall: p<0.001DX: p<0.001

APOE: not sign.Interaction: not sign.

Sign. Bonferroni Pairs (p<0.05):HC ε4-, HC ε4+, SMC ε4- > EMCI ε4-

Trend Bonferroni Pairs (p<0.1):SMC ε4- > EMCI ε4+

Overall: p<0.001DX: p<0.001

APOE: not sign.Interaction: not sign.

Sign. Bonferroni Pairs (p<0.05):HC ε4- > EMCI ε4-, EMCI ε4+

SMC ε4+ > EMCI ε4-

Trend Bonferroni Pairs (p<0.1):HC ε4+, SMC ε4- > EMCI ε4-

SMC ε4+ > EMCI ε4+Risacher SL, Kim S, Nho K, West JD, Wang Y, Petersen RC, Aisen PS, Jack CR, Jagust WJ, Koeppe RA, Weiner MW, Saykin AJ. Increased amyloid deposition in older adults at risk for progression to Alzheimer’s disease due to genetic background and/or the presence of significant memory concerns.

2014 AAIC Oral Presentation, Wednesday, July 16th; Session Title: Imaging in Mild Cognitive Impairment and Subjective Memory Complaint

IGAP Meta-Analysis: Now a “Top 20” AD Genes (2013)

Largest AD GWAS

“In addition to the APOE locus, 14 genomic regions had associations that reached genome-wide significance. 9 had been previously identified by GWAS as genetic susceptibility factors, and 5 (HLA-DRB5–HLA-DRB1, PTK2B, SORL1, SLC24A4-RIN3 and DSG2) represent newly associated loci.”

Lambert et al Nature Genetics (Oct 27, 2013)*

* ADNI data included as part of the ADGC

IGAP Meta-Analysis: Top 20 AD Genes (2013)

Embargoed: To appear 10/27/13

Lambert et al Nature Genetics (2013) Oct 27

• Loci Reinforcing Previously Implicated Pathways:– Amyloid / APP (SORL1 and CASS4); also PLD3* – Tau (CASS4 and FERMT2)– Immune response / inflammation (HLA-DRB5–DRB1, INPP5D and

MEF2C); also TREM2**– Cell migration (PTK2B)– Lipid transport and endocytosis (SORL1)

• New Pathways Associated with Alzheimer’s Disease:– Hippocampal synaptic function (MEF2C and PTK2B)– Cytoskeletal function and axonal transport (CELF1, NME8 and CASS4)– Regulation of gene expression and post-translational modification of

proteins, and microglial and myeloid cell function (INPP5D)

New Pathways: “Top 20” Genes

Lambert et al Nature Genetics (2013 Oct 27); *Cruchaga et al Nature (2013 Dec); **Guerreiro et al & Jonsson et al NEJM (2013 Jan)

Population attributable/preventive fractionsLambert et al (2013) GWAS Stage 2

Supplementary Table 6

• Illumina HiSeq Platform– Whole Exome Sequencing (WES)– Whole Genome Sequencing (WGS)– RNA Sequencing (RNA-seq / miRNA-seq)

Next Generation Sequencing

3 Letters to the Editor on TREM2

TREM2: Triggering Receptor Expressed on Myeloid Cells 2

TREM2 - ADNI MRI Atrophy Rate Study

• Rajagopalan et al (ADNI, Paul Thompson’s group) – imaging genetics analysis of annual rates of brain volume loss and the risk allele of rs9394721, a close proxy for rs75932628 in TREM2 (r2 = 0.492)

• TREM2 carriers annually lost 1.4 to 3.3% more of their brain tissue than noncarriers in an AD pattern

PLD3 WES, Family & Case Control Study (2013)

C Cruchaga et al. Nature 000, 1-5 (2013) doi:10.1038/nature12825

ADNI MRI Phenotype Association with Rare variant Val232Met in PLD3 (WGS)

K. Nho et al, AAIC 2014 & submitted

Val232MetLeft

Hemisphere

Right

Hemisphere

Bilateral

Mean

Hippocampal volume 0.0246 0.1179 0.0470

Entorhinal Cortical thickness 0.0226 0.3954 0.0945

(A) ROI-based analysis

(B) Whole brain analysis (corrected P values < 0.05)

AG GG

Exome Sequencing - Protective Effects: REST Repressor element 1-silencing transcription factor

Investigation in ADNI-1 (n=315)

Quantitative Trait Loci (QTL) analysis and surface-based analysis

rs3796529 (REST)

Effect of rs3796529 on hippocampal volume at baseline (Cross-sectional)

Effect of rs3796529 on cortical thickness at baseline (Cross-sectional)

Subjects with minor alleles of rs3796529 showed larger hippocampal volume and cortical thickness in the temporal lobe regions

Nho et al. AAIC 2013 & submitted (in revision)

Nho et al. AAIC 2013 & submitted (in revision)

REST: Meta-Analysis 5 Independent Cohorts (N=923)

Quantitative Trait loci (QTL) Association Analysis using hippocampal volume as endophenotypes

rs3796529 (REST)

Effect of rs3796529 on right hippocampal volume at baseline

Subjects with minor alleles of rs3796529 showed larger hippocampal volume

P = 0.02

Lu et al Nature 3/2014

Whole Genome Sequencing

- Data released after extensive quality control VCF files posted; BAM files portable HDs

- Realignment and recalling using a non-proprietary pipeline running for 6 months

- Coordinating with NIA/NHGRI ADSP and will implement consensus variant calling

- Early analyses of key targets (to be presented at AAIC 2014): APOE region, PSEN1, BCHE, etc.

Other Developing Areas

1) RNA - expression profiling of baseline paxgene tubes is still pending at BMS and may switch to RNA-sequencing platform

2) Metabolomics – a collaboration with the Metabolomics Network (academic and companies organized by Rima Kaddurah-Daouk, Duke Univ.) will analyze ADNI baseline data beginning with lipidomics assays

ADNI-3 Planning: Genetics CoreDraft Aims (April 2014) - Overview

• Data collection, sample banking, quality control and dissemination– Serial DNA & RNA for transcriptome and epigenetic studies

• Comprehensive and integrative data analysis– Prediction of risk; modulation of biomarker curves; systems biology

• Future directions under consideration– Studies of variants via family and follow-up studies – iPSCs – from PBMCs or fibroblasts (vs continued LCLs)– Collaborative functional genomics follow-up with PPSB members

(Nadeem Sarwar to discuss)• Continue to provide organization, collaboration and leadership

for genomic studies of quantitative biomarker phenotypes

ADNI Genetics Working GroupIndiana University • Imaging Genomics Lab

– Andrew J. Saykin– Li Shen– Sungeun Kim– Kwangsik Nho– Priya Rajagopalan– Vijay Ramanan– Shannon Risacher

• NCRAD– Tatiana M. Foroud– Kelley M. Faber

• PPSB Members– Xiaolan Hu (BMS)– Enchi Liu (Janssen)– Leanne Munsie (Lilly)– Nadeem Sarwar (Eisai)– Adam Schwarz (Lilly)– Holly Soares (BMS)– Dave Stone (Merck)– Erika Tarver (FNIH)

• Matt J. Huentelman (TGen)• Hakon Hakonarson (CHOP)• Steven G. Potkin (UC Irvine)• Core Consultants (ADNI-2):

– Lars Bertram (Max Planck)– Lindsay Farrer (BU)– Robert Green (BWH)– Jason Moore (Dartmouth)– Paul Thompson (UCLA)

• Working Group – additions (RNA, NGS)– Liana Apostolova (UCLA)– Nilufer Ertekin-Taner (Mayo Clinic)– Keoni Kauwe (BYU)– Yunlong Liu (Indiana)– Fabio Macciardi (UC Irvine) – Jill Murrell (Indiana)

2014