Key variants via Alzheimer’s Disease Sequencing Project whole genome sequence data

INTRODUCTION Genome-wide association studies (GWAS) have identified loci associated with Alzheimer’s disease (AD) but did not identify specific causal genes or variants within those loci. Analysis of whole genome sequence (WGS) data, which interrogates the entire genome and captures rare variations, may identify causal variants within GWAS loci. METHODS We performed single common variant association analysis and rare variant aggregate analyses in the pooled population (N cases=2,184, N controls=2,383) and targeted analyses in sub-populations using WGS data from the Alzheimer’s Disease Sequencing Project (ADSP). The analyses were restricted to variants within 100 kb of 83 previously identified GWAS lead variants. RESULTS Seventeen variants were significantly associated with AD within five genomic regions implicating the genes OARD1/NFYA/TREML1, JAZF1, FERMT2, and SLC24A4. KAT8 was implicated by both single variant and rare variant aggregate analyses. DISCUSSION This study demonstrates the utility of leveraging WGS to gain insights into AD loci identified via GWAS. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded through U01 AG058589 and U01 AG068221 from the National Institute on Aging. ADSP: All relevant funding is listed in the full acknowledgment statement for the ADSP that can be found at: https://dss.niagads.org/datasets/ng00067/ ADNI: Data collection and sharing for ADNI was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was done under an approved research use statement from the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) and local Institutional Review Board approval. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data from the Alzheimer's Disease Sequencing Project (ADSP) is available to qualified investigators via the National Institute on Aging Genetics of Alzheimer's Disease Data Storage Site (NIAGADS) (https://dss.niagads.org/). * (AD) : Alzheimer’s disease (ADSP) : the Alzheimer’s Disease Sequencing Project (AA) : Black/African-American (CMC) : Combined Multivariate and Collapsing (EA) : White/European-ancestry (GWAS) : Genome-Wide Association Studies (GRM) : Genetic Relationship Matrix (HI) : Hispanic/Latino (LD) : Linkage Disequilibrium (MAC) : Minor Allele Count (MAF) : Minor Allele Frequency (MCI) : Mild Cognitive Impairment (PCA) : Principal Component Analysis (QC) : Quality Control (SKAT) : Sequence Kernel Association Test (STAAR) : variant-Set Test for Association using Annotation infoRmation (WGS) : Whole Genome Sequencing