Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

被引：659

作者：

Sims, Rebecca ^{[1
]}

van der Lee, Sven J. ^{[2
]}

Naj, Adam C. ^{[3
,32
]}

Bellenguez, Celine ^{[4
,5
,6
]}

Badarinarayan, Nandini ^{[1
]}

Jakobsdottir, Johanna ^{[7
]}

Kunkle, Brian W.

Boland, Anne ^{[8
]}

Raybould, Rachel ^{[1
]}

Bis, Joshua C. ^{[9
]}

Martin, Eden R.

Grenier-Boley, Benjamin ^{[4
,5
,6
]}

Heilmann-Heimbach, Stefanie ^{[10
,11
]}

Chouraki, Vincent ^{[12
,13
]}

Kuzma, Amanda B. ^{[14
]}

Sleegers, Kristel ^{[15
,16
]}

Vronskaya, Maria ^{[1
]}

Ruiz, Agustin ^{[17
,18
]}

Graham, Robert R. ^{[19
]}

Olaso, Robert ^{[8
]}

Hoffmann, Per ^{[10
,11
,20
,21
]}

Grove, Megan L. ^{[22
]}

Vardarajan, Badri N. ^{[23
,24
,25
]}

Hiltunen, Mikko ^{[26
,27
]}

Noethen, Markus M. ^{[10
,11
]}

White, Charles C. ^{[28
]}

Hamilton-Nelson, Kara L.

Epelbaum, Jacques ^{[29
]}

Maier, Wolfgang ^{[30
,31
]}

Choi, Seung-Hoan ^{[12
,32
]}

Beecham, Gary W.

Dulary, Cecile ^{[8
]}

Herms, Stefan ^{[10
,11
,20
,21
]}

Smith, Albert V. ^{[7
,33
]}

Funk, Cory C. ^{[34
]}

Derbois, Celine ^{[8
]}

Forstner, Andreas J. ^{[10
,11
]}

Ahmad, Shahzad ^{[2
]}

Li, Hongdong ^{[34
]}

Bacq, Delphine ^{[8
]}

Harold, Denise ^{[35
]}

Satizabal, Claudia L. ^{[12
,13
]}

Valladares, Otto ^{[14
]}

Squassina, Alessio ^{[36
]}

Thomas, Rhodri ^{[1
]}

Brody, Jennifer A. ^{[9
]}

Qu, Liming ^{[14
]}

Sanchez-Juan, Pascual ^{[37
,38
,39
]}

Morgan, Taniesha ^{[1
]}

Wolters, Frank J. ^{[2
]}

机构：

[1] Cardiff Univ, MRC Ctr Neuropsychiat Genet & Gen, Inst Psychol Med & Clin Neurosci, Cardiff, S Glam, Wales

[2] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

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

[4] Risk Factors & Mol Determinants Aging Related Dis, RID AGE, U1167, INSERM, Lille, France

[5] Inst Pasteur, Lille, France

[6] Univ Lille, Excellence Lab LabEx DISTALZ, U1167, Lille, France

[7] Iceland Heart Assoc, Kopavogur, Iceland

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

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

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

[11] Univ Bonn, Life & Brain Ctr, Dept Gen, Bonn, Germany

[12] Boston Univ, Sch Med, Boston, MA 02118 USA

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

[14] Univ Penn, Sch Med, Dept Pathol & Lab Med, Penn Neurodegenerat Genom Ctr, Philadelphia, PA 19104 USA

[15] VIB, Dept Mol Genet, Neurodegenerat Brain Dis Grp, Antwerp, Belgium

[16] Univ Antwerp, Inst Born Bunge, Antwerp, Belgium

[17] Inst Catala Neurociencies Aplicades, Res Ctr, Barcelona, Spain

[18] Inst Catala Neurociencies Aplicades, Memory Clin Fundacio ACE, Barcelona, Spain

[19] Genentech Inc, Immunol Biomarkers Grp, San Francisco, CA USA

[20] Univ Basel, Div Med Genet, Univ Hosp, Basel, Switzerland

[21] Univ Basel, Dept Biomed, Basel, Switzerland

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

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

[24] Columbia Univ, Gertrude H Sergievsky Ctr, New York, NY USA

[25] Columbia Univ, Dept Neurol, New York, NY USA

[26] Univ Eastern Finland, Inst Biomed, Kuopio, Finland

[27] Kuopio Univ Hosp, Dept Neurol, Kuopio, Finland

[28] Brigham & Womens Hosp, Dept Neurol & Psychiat, Inst Neurosci, Program Translat NeuroPsychiatr Gen, Boston, MA USA

[29] Univ Paris 05, INSERM, Ctr Psychiat & Neurosci, UMR 894, Paris, France

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

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

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

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

[34] Inst Syst Biol, Seattle, WA USA

[35] Dublin City Univ, Sch Biotechnol, Dublin, Ireland

[36] Univ Cagliari, Dept Biomed Sci, Sect Neurosci & Clin Pharmacol, Cagliari, Italy

[37] Neurol Serv, Santander, Spain

[38] Univ Cantabria, Marques Valdecilla Univ Hosp, CIBERNED, Santander, Spain

[39] IFIMAV, Santander, Spain

[40] Hosp Univ Doctor Negrin, Dept Immunol, Las Palmas Gran Canaria, Spain

[41] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Houston, TX 77030 USA

[42] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA

[43] Univ Mississippi, Med Ctr, Dept Geriatr, Jackson, MS 39216 USA

[44] Univ Mississippi, Med Ctr, Dept Gerontol & Neurol, Jackson, MS 39216 USA

[45] Ctr Hos Rouvray, Sotteville Ies Rouen, France

[46] Normandy Univ, IRIB, Rouen Univ, U1079,INSERM, Rouen, France

[47] Kings Coll London, Inst Psychiat Psychol & Neurosci, Dept Basic & Clin Neurosci, London, England

[48] QIMR Berghofer Med Res Inst, Genet Epidemiol, Herston, Qld, Australia

[49] Karolinska Univ Hosp Huddinge, Dept Geriatr Med, Stockholm, Sweden

[50] Karolinska Inst, Dept Neurobiol, Care Sci & Soc, Aging Res Ctr, Stockholm, Sweden

来源：

NATURE GENETICS | 2017年 / 49卷 / 09期

基金：

欧盟地平线“2020”; 美国国家卫生研究院; 瑞典研究理事会; 加拿大健康研究院; 英国惠康基金; 芬兰科学院; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; GENOTYPE IMPUTATION; LOW-FREQUENCY; IDENTIFIES VARIANTS; COMMON VARIANTS; WAVE2; COMPLEX; LOCI; RISK; SUSCEPTIBILITY; METAANALYSIS;

D O I：

10.1038/ng.3916

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 x 10(-4)) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 x 10(-8)) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p. Pro522Arg, P = 5.38 x 10(-10), odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p. Ser209Phe, P = 4.56 x 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p. Arg62His, P = 1.55 x 10(-14), OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

引用

页码：1373 / +

页数：15

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