Key Variants via the Alzheimer's Disease Sequencing Project Whole Genome Sequence Data

Authors

Yanbing Wang
Chloé Sarnowski
Honghuang Lin
Achilleas N Pitsillides
Nancy L Heard-Costa
Seung Hoan Choi
Dongyu Wang
Joshua C Bis
Elizabeth E Blue
Eric Boerwinkle
Philip L De Jager
Myriam Fornage
Ellen M Wijsman
Sudha Seshadri
Josée Dupuis
Gina M Peloso
Anita L DeStefano

Publication Date

5-1-2024

Journal

Alzheimer's & Dementia

Abstract

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 = 2184, N controls = 2383) and targeted analyses in subpopulations 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.

Keywords

Humans, Alzheimer Disease, Genome-Wide Association Study, Whole Genome Sequencing, Female, Male, Genetic Predisposition to Disease, Aged, Polymorphism, Single Nucleotide, Genetic Variation