Association of common and rare variants with Alzheimer's disease in more than 13,000 diverse individuals with whole-genome sequencing from the Alzheimer's Disease Sequencing Project.
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Date
2024-10-20
Open Access Location
Journal Title
Journal ISSN
Volume Title
Publisher
Wiley Periodicals LLC on behalf of Alzheimer's Association
Rights
(c) 2024 The Author/s
CC BY-NC-ND 4.0
CC BY-NC-ND 4.0
Abstract
INTRODUCTION
Alzheimer's disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous.
METHODS
We investigated the association of AD with both common variants and aggregates of rare coding and non-coding variants in 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data.
RESULTS
Pooled-population analyses of all individuals identified genetic variants at apolipoprotein E (APOE) and BIN1 associated with AD (p < 5 × 10−8). Subgroup-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and non-coding variants in the region. Common variants in LINC00320 were observed associated with AD in Black individuals (p = 1.9 × 10−9). Finally, we observed rare non-coding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p = 7.2 × 10−8).
DISCUSSION
We observed that complementary pooled-population and subgroup-specific analyses offered unique insights into the genetic architecture of AD.
Highlights
We determine the association of genetic variants with Alzheimer's disease (AD) using 13,371 individuals of diverse ancestry with whole genome sequencing (WGS) data.
We identified genetic variants at apolipoprotein E (APOE), BIN1, PSEN1, and LINC00320 associated with AD.
We observed rare non-coding variants in the promoter of TOMM40 distinct of APOE.
Description
Keywords
Alzheimer's disease, genetics, rare genetic variants, whole genome sequencing
Citation
Lee W-P, Choi SH, Shea MG, Cheng P-L, Dombroski BA, Pitsillides AN, Heard-Costa NL, Wang H, Bulekova K, Kuzma AB, Leung YY, Farrell JJ, Lin H, Kunkle BW, Naj A, Blue EE, Nusetor F, Wang D, Boerwinkle E, Bush WS, Zhang X, De Jager PL, Dupuis J, Farrer LA, Fornage M, Martin E, Pericak-Vance M, Seshadri S, Wijsman EM, Wang L-S, Alzheimer's Disease Sequencing Project , Schellenberg GD, Destefano AL, Haines JL, Peloso GM. (2024). Association of common and rare variants with Alzheimer's disease in more than 13,000 diverse individuals with whole-genome sequencing from the Alzheimer's Disease Sequencing Project.. Alzheimers Dement. Early View.