Whole Genome Sequencing in Ethnically Diverse Cohorts for the ADSP Follow-Up Study (FUS)

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PROJECT SUMMARY The Alzheimer’s Disease Sequencing Project (ADSP) is a national sequencing initiative focused on identifying genetic risk and protective factors for Alzheimer’s Disease (AD) in an effort to identify new pathways for prevention and new targets for drug development. The projects’ discovery phase included whole exome sequencing (WES) of 10,914 unrelated cases (N=5,778) and controls (N=5,136) and whole genome sequencing (WGS) of 1,019 familial samples. A majority of these samples are non-Hispanic white (NHW) in origin, making the addition of ethnically diverse samples to the study critical to identification of both shared and novel genetic risk factors for AD between populations. This ethnic diversity was emphasized in the ‘ADSP Follow-Up Study (FUS) Phase’ planning stage with a directive that additional existing cohorts with unrelated AD cases that ‘encompass the richest possible ethnic diversity’ be given the highest priority for inclusion. To fulfill the goals of this RFA and this FUS Phase Mandate, this proposal identifies seven existing elderly cohorts of African-American (AA) and pan-HI ancestry with a total of 10,430 samples (N=2,322 AA AD cases and 1,843 AA controls and 2,928 Hispanic AD cases and 2,875 Hispanic controls) for WGS and processing in collaboration with existing NIH-funded AD infrastructure. Combining these cohorts with existing African America (AA) and Hispanic (HI) sequencing from the Washington Heights-Hamilton Heights-Inwood Community Aging Project (WHICAP), the Alzheimer’s Disease Genetics Consortium (ADGC) and the ADSP will provide large ethnically diverse datasets for both validation of ADSP discovery phase findings and discovery of novel risk and/or protective variants for AD. Importantly, these data will allow for admixture mapping, a powerful method of gene mapping for diseases that show differential risk by ancestry, by comparing allele frequency differences between populations. They will also become an invaluable resource for the AD research community at-large, and will help to address the health disparities that contribute to AA and HI populations having higher rates of AD than NHW. Thus, we will address these important issues by creating a large dataset of AA and pan-HI AD cases and controls for study. Specifically we propose to: 1) increase the ethnic diversity of the ADSP by assembling samples from existing cohorts with AA and HI AD cases and controls; 2) collaborate with the National Cell Repository for Alzheimer’s Disease (NCRAD) in assemblage, storage, and distribution of DNA on these cohorts; 3) generating genome-wide SNP array data and WGS for all collected samples; and 4) collaborate with the NIA Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) and The Genome Center for Alzheimer’s Disease (GCAD) in processing, quality controls, storage and distribution of the final datasets. Our overall goal is to enhance the discovery of AD risk factors by facilitating research on AD in ethnically diverse datasets.