Genetics Core Update & Planning ADNI-2 Steering Committee Philadelphia April 28, 2014 Andy Saykin Indiana University

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<0.001 DX: p=0.009 APOE: p<0.001 Interaction: 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<0.001 DX: p=0.006 APOE: p<0.001 Interaction: 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 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=0.013 DX: not sign. APOE: not sign. Interaction: p=0.030 Sign. Bonferroni Pairs (p<0.05): EMCI ε4- > EMCI ε4+ Overall: p=0.004 DX: 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 AAIC Oral Presentation, Wednesday, July 16 th ; Session Title: Imaging in Mild Cognitive Impairment and Subjective Memory Complaint

Neurodegeneration (Hippocampus): Diagnosis vs APOE ε4 Status Overall: p<0.001 DX: 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<0.001 DX: 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 AAIC Oral Presentation, Wednesday, July 16 th ; 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 fractions Lambert 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 rs , a close proxy for rs 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: /nature12825

ADNI MRI Phenotype Association with Rare variant Val232Met in PLD3 (WGS) K. Nho et al, AAIC 2014 & submitted Val232Met Left Hemisphere Right Hemisphere Bilateral Mean Hippocampal volume Entorhinal Cortical thickness (A) ROI-based analysis (B) Whole brain analysis (corrected P values < 0.05) AGGG

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 rs (REST) Effect of rs on hippocampal volume at baseline (Cross-sectional) Effect of rs on cortical thickness at baseline (Cross-sectional) Subjects with minor alleles of rs showed larger hippocampal volume and cortical thickness in the temporal lobe regions 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 rs (REST) Effect of rs on right hippocampal volume at baseline Subjects with minor alleles of rs 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 Core Draft 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 Group Indiana 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