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

被引：2

作者：

Lee, Wan-Ping ^{[1
,2
]}

Choi, Seung Hoan ^{[3
]}

Shea, Margaret G. ^{[4
]}

Cheng, Po-Liang ^{[1
,2
]}

Dombroski, Beth A. ^{[1
]}

Pitsillides, Achilleas N. ^{[3
]}

Heard-Costa, Nancy L. ^{[5
,6
]}

Wang, Hui ^{[1
,2
]}

Bulekova, Katia ^{[7
]}

Kuzma, Amanda B. ^{[1
,2
]}

Leung, Yuk Yee ^{[1
,2
]}

Farrell, John J. ^{[8
]}

Lin, Honghuang ^{[9
]}

Kunkle, Brian W. ^{[10
,11
]}

Naj, Adam ^{[12
]}

Blue, Elizabeth E. ^{[13
,14
]}

Nusetor, Frederick ^{[3
]}

Wang, Dongyu ^{[3
]}

Boerwinkle, Eric ^{[15
,16
]}

Bush, William S. ^{[17
,18
]}

Zhang, Xiaoling ^{[3
,8
]}

De Jager, Philip L. ^{[19
]}

Dupuis, Josee ^{[3
,20
]}

Farrer, Lindsay A. ^{[3
,5
,6
,8
,21
,22
]}

Fornage, Myriam ^{[23
,24
]}

Martin, Eden ^{[10
,11
,25
]}

Pericak-Vance, Margaret ^{[10
,11
,25
]}

Seshadri, Sudha ^{[26
]}

Wijsman, Ellen M. ^{[13
,27
,28
]}

Wang, Li-San ^{[1
,2
]}

Schellenberg, Gerard D. ^{[1
,2
]}

Destefano, Anita L. ^{[3
,5
]}

Haines, Jonathan L. ^{[17
,18
]}

Peloso, Gina M. ^{[3
]}

机构：

[1] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA USA

[2] Univ Penn, Penn Neurodegenerat Genom Ctr, Perelman Sch Med, Philadelphia, PA USA

[3] Boston Univ, Sch Publ Hlth, Dept Biostat, 800 Massachusetts Ave, Boston, MA 02118 USA

[4] Boston Univ, Sch Publ Hlth, Biostat & Epidemiol Data Analyt Ctr, Boston, MA USA

[5] Boston Univ, Chobanian & Avedisian Sch Med, Dept Neurol, Boston, MA USA

[6] Framingham Heart Dis Epidemiol Study, Framingham, MA USA

[7] Boston Univ, Res Comp Serv Informat Serv & Technol, Boston, MA USA

[8] Boston Univ, Biomed Genet, Med Sch, Dept Med, Boston, MA USA

[9] Univ Massachusetts, Chan Med Sch, Dept Med, Worcester, MA USA

[10] Univ Miami, Miami, FL USA

[11] Univ Miami, Miami, FL USA

[12] Univ Penn, Perelman Sch Med, Dept Biostat Epidemiol & Informat, Dept Pathol, Philadelphia, PA USA

[13] Univ Washington, Dept Med, Div Med Genet, Seattle, WA USA

[14] Brotman Baty Inst Precis Med, Seattle, WA USA

[15] Univ Texas Hlth Sci Ctr Houston, Dept Epidemiol Human Genet & Environm Sci, Sch Publ Hlth, Houston, TX USA

[16] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX USA

[17] Cleveland Inst Computat Biol, Cleveland, OH USA

[18] Case Western Reserve Univ, Dept Populat & Quantitat Hlth Sci, Cleveland, OH USA

[19] Columbia Univ, Med Ctr, Ctr Translat & Computat Neuroimmunol, New York, NY USA

[20] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada

[21] Boston Univ, Dept Med, Sch Med, Boston, MA USA

[22] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[23] Univ Texas Hlth Sci Ctr Houston, Brown Fdn, McGovern Med Sch, Inst Mol Med, Houston, TX USA

[24] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Sch Publ Hlth, Houston, TX USA

[25] Univ Miami, Miller Sch Med, Miami, FL USA

[26] Univ Texas Hlth Sci Ctr San Antonio, Glenn Biggs Inst Alzheimers & Neurodegenerat Dis, San Antonio, TX USA

[27] Univ Washington, Dept Biostat, Seattle, WA USA

[28] Univ Washington, Dept Genome Sci, Seattle, WA USA

来源：

ALZHEIMERS & DEMENTIA | 2024年

关键词：

Alzheimer's disease; genetics; rare genetic variants; whole genome sequencing; APOLIPOPROTEIN-E; WIDE ASSOCIATION; RISK LOCI; MUTATIONS; ABCA7; GENE; MECHANISMS; GENOTYPE; ALLELE; COHORT;

D O I：

10.1002/alz.14283

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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 x 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 x 10(-9)). Finally, we observed rare non-coding variants in the promoter of TOMM40 distinct of APOE in pooled-population analyses (p = 7.2 x 10(-8)). DISCUSSION We observed that complementary pooled-population and subgroup-specific analyses offered unique insights into the genetic architecture of AD.

引用

页码：8470 / 8483

页数：14

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