Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.
Nalls MA., Pankratz N., Lill CM., Do CB., Hernandez DG., Saad M., DeStefano AL., Kara E., Bras J., Sharma M., Schulte C., Keller MF., Arepalli S., Letson C., Edsall C., Stefansson H., Liu X., Pliner H., Lee JH., Cheng R., International Parkinson's Disease Genomics Consortium (IPDGC) None., Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI) None., 23andMe None., GenePD None., NeuroGenetics Research Consortium (NGRC) None., Hussman Institute of Human Genomics (HIHG) None., Ashkenazi Jewish Dataset Investigator None., Cohorts for Health and Aging Research in Genetic Epidemiology (CHARGE) None., North American Brain Expression Consortium (NABEC) None., United Kingdom Brain Expression Consortium (UKBEC) None., Greek Parkinson's Disease Consortium None., Alzheimer Genetic Analysis Group None., Ikram MA., Ioannidis JPA., Hadjigeorgiou GM., Bis JC., Martinez M., Perlmutter JS., Goate A., Marder K., Fiske B., Sutherland M., Xiromerisiou G., Myers RH., Clark LN., Stefansson K., Hardy JA., Heutink P., Chen H., Wood NW., Houlden H., Payami H., Brice A., Scott WK., Gasser T., Bertram L., Eriksson N., Foroud T., Singleton AB.
We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.