TY - JOUR
T1 - Imputation of sequence variants for identification of genetic risks for Parkinson's disease
T2 - A meta-analysis of genome-wide association studies
AU - Nalls, Michael A.
AU - Plagnol, Vincent
AU - Hernandez, Dena G.
AU - Sharma, Manu
AU - Sheerin, Una Marie
AU - Saad, Mohamad
AU - Simón-Sánchez, J.
AU - Schulte, Claudia
AU - Lesage, Suzanne
AU - Sveinbjörnsdóttir, Sigurlaug
AU - Stefánsson, Kári
AU - Martinez, Maria
AU - Hardy, John
AU - Heutink, Peter
AU - Brice, Alexis
AU - Gasser, Thomas
AU - Singleton, Andrew B.
AU - Wood, Nicholas W.
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=79951811351&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(10)62345-8
DO - 10.1016/S0140-6736(10)62345-8
M3 - Article
C2 - 21292315
AN - SCOPUS:79951811351
SN - 0140-6736
VL - 377
SP - 641
EP - 649
JO - The Lancet
JF - The Lancet
IS - 9766
ER -