Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease

被引：3152

作者：

Lambert, Jean-Charles ^{[1
,2
,3
]}

Ibrahim-Verbaas, Carla A. ^{[4
,5
]}

Harold, Denise ^{[6
]}

Naj, Adam C. ^{[7
,8
]}

Sims, Rebecca ^{[6
]}

Bellenguez, Celine ^{[1
,2
,3
]}

Jun, Gyungah ^{[9
,10
,11
]}

DeStefano, Anita L. ^{[11
]}

Bis, Joshua C. ^{[12
]}

Beecham, Gary W. ^{[13
,14
]}

Grenier-Boley, Benjamin ^{[1
,2
,3
]}

Russo, Giancarlo ^{[15
]}

Thornton-Wells, Tricia A. ^{[16
]}

Jones, Nicola ^{[6
]}

Smith, Albert V. ^{[17
,18
]}

Chouraki, Vincent ^{[1
,2
,3
]}

Thomas, Charlene ^{[6
]}

Ikram, M. Arfan ^{[4
,5
,19
,20
]}

Zelenika, Diana ^{[21
]}

Vardarajan, Badri N. ^{[9
]}

Kamatani, Yoichiro ^{[22
]}

Lin, Chiao-Feng ^{[23
]}

Gerrish, Amy ^{[6
]}

Schmidt, Helena ^{[24
]}

Kunkle, Brian ^{[13
]}

Dunstan, Melanie L. ^{[6
]}

Ruiz, Agustin ^{[25
]}

Bihoreau, Marie-Therese ^{[21
]}

Choi, Seung-Hoan ^{[11
]}

Reitz, Christiane ^{[26
,27
]}

Pasquier, Florence ^{[2
,28
]}

Hollingworth, Paul ^{[6
]}

Ramirez, Alfredo ^{[29
,30
]}

Hanon, Olivier ^{[31
]}

Fitzpatrick, Annette L. ^{[12
,32
,33
]}

Buxbaum, Joseph D. ^{[34
,35
,36
]}

Campion, Dominique ^{[37
]}

Crane, Paul K. ^{[38
]}

Baldwin, Clinton ^{[9
]}

Becker, Tim ^{[39
,40
]}

Gudnason, Vilmundur ^{[17
,18
]}

Cruchaga, Carlos ^{[41
,42
]}

Craig, David ^{[43
]}

Amin, Najaf ^{[5
]}

Berr, Claudine ^{[44
]}

Lopez, Oscar L. ^{[45
]}

De Jager, Philip L. ^{[46
,47
,48
]}

Deramecourt, Vincent ^{[2
,28
]}

Johnston, Janet A. ^{[43
]}

Evans, Denis ^{[49
]}

机构：

[1] INSERM, U744, F-59045 Lille, France

[2] Univ Lille 2, Lille, France

[3] Inst Pasteur, F-59019 Lille, France

[4] Erasmus MC Univ Med Ctr, Dept Neurol, Rotterdam, Netherlands

[5] Erasmus MC Univ Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[6] Cardiff Univ, Inst Psychol Med & Clin Neurosci, MRC, Ctr Neuropsychiat Genet & Genom, Cardiff CF10 3AX, S Glam, Wales

[7] Univ Penn, Dept Biostat & Epidemiol, Perelman Sch Med, Philadelphia, PA 19104 USA

[8] Univ Penn, Ctr Clin Epidemiol & Biostat, Perelman Sch Med, Philadelphia, PA 19104 USA

[9] Boston Univ, Sch Publ Hlth, Dept Med Biomed Genet, Boston, MA USA

[10] Boston Univ, Sch Med, Dept Ophthalmol, Boston, MA 02118 USA

[11] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[12] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[13] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA

[14] Univ Miami, Dept Human Genet, Dr John T Macdonald Fdn, Miami, FL USA

[15] Univ Zurich, ETH, Funct Genom Ctr Zurich, Zurich, Switzerland

[16] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA

[17] Univ Iceland, Fac Med, Reykjavik, Iceland

[18] Iceland Heart Assoc, Kopavogur, Iceland

[19] Erasmus MC Univ Med Ctr, Dept Radiol, Rotterdam, Netherlands

[20] Netherlands Consortium Hlth Aging, Leiden, Netherlands

[21] CEA, Inst Genom, Ctr Natl Genotypage, Evry, France

[22] Fdn Jean Dausset, Ctr Etud Polymorphisme Humain, Paris, France

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

[24] Med Univ Graz, Inst Mol Biol & Biochem, Graz, Austria

[25] Memory Clin Fundacio Alzheimer Ctr Educ ACF, Inst Catala Neurociencies Aplicades, Barcelona, Spain

[26] Columbia Univ, Dept Neurol, Taub Inst Alzheimers Dis & Aging Brain, New York, NY USA

[27] Columbia Univ, Gertrude H Sergievsky Ctr, Dept Neurol, New York, NY 10027 USA

[28] Ctr Hosp Reg Univ Lille, CNR MAJ, Lille, France

[29] Univ Bonn, Dept Psychiat & Psychotherapy, Bonn, Germany

[30] Univ Bonn, Inst Human Genet, Bonn, Germany

[31] Univ Paris 05, Broca Hosp, Dept Geriatr, Paris, France

[32] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA

[33] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA

[34] Mt Sinai Sch Med, Dept Neurosci, New York, NY USA

[35] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA

[36] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA

[37] Rouen Univ Hosp, INSERM, CNR MAJ, U1079, Rouen, France

[38] Univ Washington, Dept Med, Seattle, WA USA

[39] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany

[40] Univ Bonn, Inst Med Biometry Informat & Epidemiol, Bonn, Germany

[41] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA

[42] Washington Univ, Sch Med, Hope Ctr Program Prot Aggregat & Neurodegenerat, St Louis, MO USA

[43] Queens Univ Belfast, Ageing Grp, Ctr Publ Hlth, Sch Med Dent & Biomed Sci, Belfast, Antrim, North Ireland

[44] Hop La Colombiere, Fac Med, U1061, INSERM, Montpellier, France

[45] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA

[46] Brigham & Womens Hosp, Dept Neurol & Psychiat, Inst Neurosci, Program Translat NeuroPsychiat Genom, Boston, MA 02115 USA

[47] Harvard Univ, Sch Med, Boston, MA USA

[48] Broad Inst, Program Med & Populat Genet, Boston, MA USA

[49] Rush Univ, Med Ctr, Dept Internal Med, Rush Inst Hlth Aging, Chicago, IL 60612 USA

[50] Univ London, Kings Coll London, Inst Psychiat, London SW3 6LX, England

来源：

NATURE GENETICS | 2013年 / 45卷 / 12期

基金：

英国惠康基金; 美国国家卫生研究院;

关键词：

GENOME-WIDE ASSOCIATION; COMMON VARIANTS; GENETIC RISK; RECEPTOR; CD33; IMPUTATION; MUTATIONS; GENOTYPES; SEQUENCE; NEURONS;

D O I：

10.1038/ng.2802

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 x 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

引用

页码：1452 / U206

页数：9

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