Missense and loss-of-function variants at GWAS loci in familial Alzheimer's disease

被引:0
作者
Gunasekaran, Tamil Iniyan [1 ,2 ]
Reyes-Dumeyer, Dolly [1 ,2 ]
Faber, Kelley M. [3 ]
Goate, Alison [4 ]
Boeve, Brad [5 ]
Cruchaga, Carlos [6 ]
Pericak-Vance, Margaret [7 ]
Haines, Jonathan L. [8 ,9 ]
Rosenberg, Roger [10 ]
Tsuang, Debby [11 ]
Mejia, Diones Rivera [12 ,13 ]
Medrano, Martin [14 ]
Lantigua, Rafael A. [1 ,2 ,15 ,16 ]
Sweet, Robert A. [17 ,18 ]
Bennett, David A. [19 ]
Wilson, Robert S. [19 ]
Alba, Camille [20 ]
Dalgard, Clifton [20 ]
Foroud, Tatiana [3 ]
Vardarajan, Badri N. [1 ,2 ]
Mayeux, Richard [1 ,2 ]
机构
[1] Columbia Univ, Taub Inst Res Alzheimers Dis & Aging Brain, Dept Neurol, New York, NY 10032 USA
[2] Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY 10032 USA
[3] Indiana Univ Sch Med, Natl Centralized Repository Alzheimers Dis & Rela, Dept Med & Mol Genet, 410W 10th St,HS 4000, Indianapolis, IN USA
[4] Icahn Sch Med Mt Sinai, Ronald M Loeb Ctr Alzheimers Dis, Dept Genet & Genom Sci, Icahn Bldg,1 Gustave L Levy Pl, New York, NY USA
[5] Mayo Clin, Dept Neurol, Rochester, MN USA
[6] Washington Univ St Louis, Dept Psychiat, 600 S Euclid Ave,Wohl Hosp Bldg, St Louis, MO USA
[7] Univ Miami, Miller Sch Med, Dr John T Macdonald Fdn Dept Human Genet, John P Hussman Inst Human Gen, Miami, FL USA
[8] Case Western Reserve Univ, Dept Populat & Quantitat Hlth Sci, Cleveland, OH USA
[9] Case Western Reserve Univ, Cleveland Inst Computat Biol, Cleveland, OH USA
[10] Univ Texas Southwestern Med Ctr Dallas, Dept Neurol, Dallas, TX USA
[11] Univ Washington, Dept Psychiat & Behav Sci, GRECC VA Puget Sound, 1660 South Columbian Way, Seattle, WA USA
[12] Ctr Diagnost & Med Avanzada & Conferencias Med &, Plaza Salud,Dr Juan Manuel Taveras Rodriguez,C Pe, Santo Domingo, Dominican Rep
[13] Univ Pedro Henriquez Urena, Ave John F Kennedy Km 7-1-2,Santo Domingo 1423, Santo Domingo, Dominican Rep
[14] Pontificia Univ Catolica Madre Maestra PUCMM, Autopista Duarte Km 1-1-2, Santiago De Los Caballer, Dominican Rep
[15] Columbia Univ, Coll Physicians & Surg, Dept Med Vagelos, New York, NY USA
[16] New York Presbyterian Hosp, New York, NY USA
[17] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA
[18] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA USA
[19] Rush Univ Med Ctr, Rush Alzheimers Dis Ctr, 1750 West Harrison St, Chicago, IL USA
[20] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD USA
基金
美国国家卫生研究院;
关键词
familial Alzheimer's disease; gene loci; genetic segregation; genome wide association studies; rare variants; NATIONAL INSTITUTE; NEUROPATHOLOGIC ASSESSMENT; ASSOCIATION GUIDELINES; CARIBBEAN HISPANICS; COMMON VARIANTS; RISK; GENE; MUTATIONS; DEMENTIA; EPSILON-4;
D O I
10.1002/alz.14221
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
BACKGROUND: Few rare variants have been identified in genetic loci from genome-wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling. METHODS: Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS: Eighty-six rare missense or loss-of-function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E (APOE)-epsilon 4 was the only variant segregating. However, in 60.3% of families, APOE ?4, missense, and LoF variants were not found within the GWAS loci. DISCUSSION: Although APOE epsilon 4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants.
引用
收藏
页码:7580 / 7594
页数:15
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