Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies

被引：712

作者：

Nalls, Michael A. ^{[1
]}

Plagnol, Vincent ^{[2
]}

Hernandez, Dena G. ^{[3
]}

Sharma, Manu ^{[4
,5
]}

Sheerin, Una-Marie ^{[3
]}

Saad, Mohamad ^{[6
,7
]}

Simon-Sanchez, Javier ^{[8
]}

Schulte, Claudia

Lesage, Suzanne ^{[9
,10
,11
]}

Sveinbjornsdottir, Sigurlaug ^{[12
,13
,14
]}

Arepalli, Sampath

Barker, Roger ^{[15
]}

Ben-Shlomo, Yoav ^{[16
]}

Berendse, Henk W. ^{[17
,18
]}

Berg, Daniela

Bhatia, Kailash ^{[3
]}

de Bie, Rob M. A. ^{[19
]}

Biffi, Alessandro ^{[20
,21
,22
]}

Bloem, Bas ^{[23
]}

Bochdanovits, Zoltan ^{[8
]}

Bonin, Michael ^{[24
]}

Bras, Jose M. ^{[3
]}

Brockmann, Kathrin

Brooks, Janet

Burn, David J. ^{[25
]}

Charlesworth, Gavin ^{[3
]}

Chen, Honglei ^{[26
]}

Chinnery, Patrick F. ^{[27
]}

Chong, Sean

Clarke, Carl E. ^{[28
,29
]}

Cookson, Mark R.

Cooper, J. Mark ^{[30
]}

Corvol, Jean Christophe ^{[9
,11
,31
]}

Counsell, Carl ^{[32
]}

Damier, Philippe ^{[33
]}

Dartigues, Jean-Francois ^{[34
]}

Deloukas, Panos ^{[35
]}

Deuschl, Guenther ^{[36
]}

Dexter, David T. ^{[37
]}

van Dijk, Karin D. ^{[17
,18
]}

Dillman, Allissa

Durif, Frank ^{[38
]}

Duerr, Alexandra ^{[9
,11
,39
]}

Edkins, Sarah ^{[35
]}

Evans, Jonathan R. ^{[40
]}

Foltynie, Thomas

Gao, Jianjun

Gardner, Michelle ^{[3
]}

Gibbs, J. Raphael ^{[3
]}

Goate, Alison

机构：

[1] NIA, Neurogenet Lab, NIH, Bethesda, MD 20837 USA

[2] UCL Genet Inst, London, England

[3] UCL Inst Neurol, Dept Mol Neurosci, London, England

[4] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany

[5] German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany

[6] CPTP, INSERM, U563, Toulouse, France

[7] Univ Toulouse 3, F-31062 Toulouse, France

[8] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Sect Med Genom, Amsterdam, Netherlands

[9] INSERM, UMR S975, Paris, France

[10] Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, Paris, France

[11] CNRS, Paris, France

[12] Landspitali Univ Hosp, Dept Neurol, Reykjavik, Iceland

[13] MEHT Broomfield Hosp, Dept Neurol, Chelmsford, Essex, England

[14] Univ London, Queen Mary Coll, London, England

[15] Univ Cambridge, Addenbrookes Hosp, Dept Neurol, Cambridge CB2 2QQ, England

[16] Univ Bristol, Dept Social Med, Bristol BS8 1TH, Avon, England

[17] Vrije Univ Amsterdam Med Ctr, Dept Neurol, Amsterdam, Netherlands

[18] Vrije Univ Amsterdam Med Ctr, Alzheimers Ctr, Amsterdam, Netherlands

[19] Univ Amsterdam, Acad Med Ctr, Dept Neurol, NL-1105 AZ Amsterdam, Netherlands

[20] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[21] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[22] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA

[23] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, NL-6525 ED Nijmegen, Netherlands

[24] Univ Tubingen, Inst Human Genet, Dept Med Genet, Tubingen, Germany

[25] Newcastle Univ, Clin Ageing Res Unit, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[26] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC USA

[27] Newcastle Univ, Sch Med, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[28] Univ Birmingham, Sch Clin & Expt Med, Birmingham, W Midlands, England

[29] Sandwell & W Birmingham Hosp NHS Trust, City Hosp, Dept Neurol, Birmingham, W Midlands, England

[30] UCL Inst Neurol, Dept Clin Neurosci, London, England

[31] Hop La Pitie Salpetriere, INSERM, CIC 9503, Paris, France

[32] Univ Aberdeen, Div Appl Hlth Sci, Populat Hlth Sect, Aberdeen, Scotland

[33] CHU Nantes, CIC0004, Serv Neurol, F-44035 Nantes 01, France

[34] Univ Victor Segalen, INSERM, U897, Bordeaux, France

[35] Wellcome Trust Sanger Inst, Cambridge, England

[36] Univ Kiel, Univ Klinikum Schleswig Holstein, Neurol Klin, Kiel, Germany

[37] Univ London Imperial Coll Sci Technol & Med, Fac Med, Parkinsons Dis Res Grp, London, England

[38] Hop Gabriel Montpied, Serv Neurol, Clermont Ferrand, France

[39] Hop La Pitie Salpetriere, AP HP, Paris, France

[40] Cambridge Ctr Brain Repair, Cambridge, England

[41] Oslo Univ Hosp, deCODE Genet, N-0407 Oslo, Norway

[42] Oslo Univ Hosp, Dept Psychiat, N-0407 Oslo, Norway

[43] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands

[44] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands

[45] AARP, Washington, DC USA

[46] UCL Inst Neurol, Queen Sq Brain Bank Neurol Disorders, London, England

[47] John Radcliffe Hosp, Dept Clin Neurol, Oxford OX3 9DU, England

[48] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA

[49] Penn State Univ, Milton S Hershey Med Ctr, Dept Radiol, Hershey, PA 17033 USA

[50] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA 17033 USA

来源：

LANCET | 2011年 / 377卷 / 9766期

基金：

美国国家卫生研究院; 英国医学研究理事会; 英国惠康基金;

关键词：

COMMON; LOCI; SUGGESTS; REGION; STK39;

D O I：

10.1016/S0140-6736(10)62345-8

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Background Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. Methods We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. Findings The discovery phase consisted of 5333 case and 12 019 control samples, with genotyped and imputed data at 7 689 524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p<5x10(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BSTI, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60.3% (95% CI 43.7-69-3). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2.51 (95% CI 2.23-2.83) compared with 1.00 in the lowest quintile of disease risk. Interpretation These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies.

引用

页码：641 / 649

页数：9

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