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 [preprint]
Lee, Wan-Ping ; Choi, Seung Hoan ; Shea, Margaret G ; Cheng, Po-Liang ; Dombroski, Beth A ; Pitsillides, Achilleas N ; Heard-Costa, Nancy L ; Wang, Hui ; Bulekova, Katia ; Kuzma, Amanda B ... show 10 more
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Choi, Seung Hoan
Shea, Margaret G
Cheng, Po-Liang
Dombroski, Beth A
Pitsillides, Achilleas N
Heard-Costa, Nancy L
Wang, Hui
Bulekova, Katia
Kuzma, Amanda B
Leung, Yuk Yee
Farrell, John J
Lin, Honghuang
Naj, Adam
Blue, Elizabeth E
Nusetor, Frederick
Wang, Dongyu
Boerwinkle, Eric
Bush, William S
Zhang, Xiaoling
De Jager, Philip L
Dupuis, Josée
Farrer, Lindsay A
Fornage, Myriam
Martin, Eden
Pericak-Vance, Margaret
Seshadri, Sudha
Wijsman, Ellen M
Wang, Li-San
Schellenberg, Gerard D
Destefano, Anita L
Haines, Jonathan L
Peloso, Gina M
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Abstract
Alzheimer's 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 < 5×10-8). 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 < 5×10-5) of aggregates of rare coding rare variants in ABCA7 among non-Hispanic Whites (p=5.4×10-6), and rare noncoding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p=7.2×10-8). Complementary pooled-population and population-specific analyses offered unique insights into the genetic architecture of AD.
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Lee WP, Choi SH, Shea MG, Cheng PL, Dombroski BA, Pitsillides AN, Heard-Costa NL, Wang H, Bulekova K, Kuzma AB, Leung YY, Farrell JJ, Lin H, 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 LS, Schellenberg GD, Destefano AL, Haines JL, Peloso GM. 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. medRxiv [Preprint]. 2023 Sep 2:2023.09.01.23294953. doi: 10.1101/2023.09.01.23294953. PMID: 37693521; PMCID: PMC10491367.
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This article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.