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

Michael A. Nalls, Vincent Plagnol, Dena G. Hernandez, Manu Sharma, Una Marie Sheerin, Mohamad Saad, J. Simón-Sánchez, Claudia Schulte, Suzanne Lesage, Sigurlaug Sveinbjörnsdóttir, Kári Stefánsson, Maria Martinez, John Hardy, Peter Heutink, Alexis Brice, Thomas Gasser, Andrew B. Singleton, Nicholas W. Wood

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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 12019 control samples, with genotyped and imputed data at 7689524 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<5×10-8). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BST1, 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. Funding: Wellcome Trust, National Institute on Aging, and US Department of Defense.

Original languageEnglish
Pages (from-to)641-649
Number of pages9
JournalThe Lancet
Volume377
Issue number9766
DOIs
Publication statusPublished - 19 Feb 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Nalls, M. A., Plagnol, V., Hernandez, D. G., Sharma, M., Sheerin, U. M., Saad, M., Simón-Sánchez, J., Schulte, C., Lesage, S., Sveinbjörnsdóttir, S., Stefánsson, K., Martinez, M., Hardy, J., Heutink, P., Brice, A., Gasser, T., Singleton, A. B., & Wood, N. W. (2011). Imputation of sequence variants for identification of genetic risks for Parkinson's disease: A meta-analysis of genome-wide association studies. The Lancet, 377(9766), 641-649. https://doi.org/10.1016/S0140-6736(10)62345-8