Association of Common and Rare Variants with Alzheimer's Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer's Disease Sequencing Project

Wan‐Ping Lee; Seung Hoan Choi; Margaret G. Shea; Po‐Liang Cheng; Beth A. Dombroski; Achilleas Pitsillides; Nancy L. Heard‐Costa; Hui Wang; Katia Bulekova; Amanda B Kuzma; Yuk Yee Leung; John J. Farrell; Honghuang Lin; Brian W. Kunkle; Adam Christian Naj; Elizabeth Blue; Frederick Nusetor; Dongyu Wang; Eric Boerwinkle; William S. Bush; Xiaoling Zhang; Philip L. De Jager; Josée Dupuis; Lindsay A. Farrer; Myriam Fornage; Eden R. Martin; Margaret Ann Pericak‐Vance; Sudha S. Seshadri; Ellen M. Wijsman; Li‐San Wang

doi:10.1002/alz.14283

Genetic & Genomic MedicineAlzheimer s & DementiaOct 20, 2024

Peer-reviewed journal article

Association of Common and Rare Variants with Alzheimer's Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer's Disease Sequencing Project

Wan‐Ping Lee iD, Seung Hoan Choi iD, Margaret G. Shea iD, Po‐Liang Cheng iD, Beth A. Dombroski iD, Achilleas Pitsillides iD, Nancy L. Heard‐Costa iD, Hui Wang iD, Katia Bulekova iD, Amanda B Kuzma iD, Yuk Yee Leung iD, John J. Farrell iD, Honghuang Lin iD, Brian W. Kunkle iD, Adam Christian Naj iD, Elizabeth Blue iD, Frederick Nusetor, Dongyu Wang iD, Eric Boerwinkle iD, William S. Bush iD, Xiaoling Zhang iD, Philip L. De Jager iD, Josée Dupuis iD, Lindsay A. Farrer iD, Myriam Fornage iD, , Gina Marie Peloso iD

Abstract

Alzheimers Disease (AD) is a common disorder of the elderly that is both highly heritable and genetically heterogeneous. Here, we investigated the association between AD and both common variants and aggregates of rare coding and noncoding variants in 13,371 individuals of diverse ancestry with whole genome sequence (WGS) data. Pooled-population analyses identified genetic variants in or near APOE, BIN1, and LINC00320 significantly associated with AD (p < 5x10-8). Population-specific analyses identified a haplotype on chromosome 14 including PSEN1 associated with AD in Hispanics, further supported by aggregate testing of rare coding and noncoding variants in this region. Finally, we observed suggestive associations (p < 5x10-5) of aggregates of rare coding rare variants in ABCA7 among non-Hispanic Whites (p=5.4x10-6), and rare noncoding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p=7.2x10-8). Complementary pooled-population and population-specific analyses offered unique insights into the genetic architecture of AD.

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