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

Lookup NU author(s): Professor David Burn, Professor Patrick Chinnery, Dr Gavin Hudson

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Abstract

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.


Publication metadata

Author(s): Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin UM, Saad M, Simon-Sanchez J, Schulte C, Lesage S, Sveinbjornsdottir S, Arepalli S, Barker R, Ben-Shlomo Y, Berendse HW, Berg D, Bhatia K, de Bie RMA, Biffi A, Bloem B, Bochdanovits Z, Bonin M, Bras JM, Brockmann K, Brooks J, Burn DJ, Charlesworth G, Chen HL, Chinnery PF, Chong S, Clarke CE, Cookson MR, Cooper JM, Corvol JC, Counsell C, Damier P, Dartigues JF, Deloukas P, Deuschl G, Dexter DT, van Dijk KD, Dillman A, Durif F, Durr A, Edkins S, Evans JR, Foltynie T, Gao JJ, Gardner M, Gibbs JR, Goate A, Gray E, Guerreiro R, Gustafsson O, Harris C, van Hilten JJ, Hofman A, Hollenbeck A, Holton J, Hu M, Huang XM, Huber H, Hudson G, Hunt SE, Huttenlocher J, Illig T, Jonsson PV, Lambert JC, Langford C, Lees A, Lichtner P, Limousin P, Lopez G, Lorenz D, McNeill A, Moorby C, Moore M, Morris HR, Morrison KE, Mudanohwo E, O'Sullivan SS, Pearson J, Perlmutter JS, Petursson H, Pollak P, Post B, Potter S, Ravina B, Revesz T, Riess O, Rivadeneira F, Rizzu P, Ryten M, Sawcer S, Schapira A, Scheffer H, Shaw K, Shoulson I, Sidransky E, Smith C, Spencer CCA, Stefansson H, Stockton JD, Strange A, Talbot K, Tanner CM, Tashakkori-Ghanbaria A, Tison F, Trabzuni D, Traynor BJ, Uitterlinden AG, Velseboer D, Vidailhet M, Walker R, van de Warrenburg B, Wickremaratchi M, Williams N, Williams-Gray CH, Winder-Rhodes S, Stefansson K, Martinez M, Hardy J, Heutink P, Brice A, Gasser T, Singleton AB, Wood NW, Int Parkinson Dis Genomics Consort, Wellcome Trust Case-Control Consor

Publication type: Article

Publication status: Published

Journal: Lancet

Year: 2011

Volume: 377

Issue: 9766

Pages: 641-649

Print publication date: 01/02/2011

ISSN (print): 0140-6736

ISSN (electronic): 1474-547X

Publisher: The Lancet Publishing Group

URL: http://dx.doi.org/10.1016/S0140-6736(10)62345-8

DOI: 10.1016/S0140-6736(10)62345-8


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Funding

Funder referenceFunder name
American Parkinson disease Association (APDA)
Cephalon
deCODE
Eisai
Hersenstichting Nederland
Novartis
Parkinson's Disease Consortium (UKPDC)
Prinses Beatrix Fonds
section of medical genomics
Barnes Jewish Hospital Foundation
Department of Health's National Institute for Health Research Biomedical Research Centres
Forschungszentrum fur Umwelt und Gesundheit
Greater St Louis Chapter of the APDA
Helmholtz Association
Icelandic Research Council
Landspitali University Hospital
Medical Research Council
Merck-Serono
National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences
Neuroscience Campus Amsterdam
01GS08134German National Genome Network (German Ministry for Education and Research)
083948/Z/07/ZWellcome Trust
8047Parkinson's UK
ANR-08-MNP-012French National Agency of Research
G0700943Medical Research Council
HA-215Helmholtz Alliance Mental Health in an Ageing Society
J-0804Parkinson's UK
NGFN 01GR0468German Federal Ministry of Education and Research
NS057105National Institutes of Health
PIAP-GA-2008-230596European Community
W81XWH-09-2-0128US Department of Defense
WT089698/Z/09/ZWellcome Trust disease centre
RA024992National Institutes of Health
Z01-AG000949-02National Human Genome Research Institute of the National Institutes of Health, Department of Health and Human Services
WT089698Wellcome Trust/Medical Research Council
Z01-ES101986National Human Genome Research Institute of the National Institutes of Health, Department of Health and Human Services

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