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Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

2014; Nature Portfolio; Volume: 46; Issue: 9 Linguagem: Inglês

10.1038/ng.3043

1546-1718

Mike A. Nalls, Nathan Pankratz, Christina M. Lill, Joshua Shulman, Dena G. Hernandez, Mohamad Saad, Anita L. DeStefano, Eleanna Kara, José Brás, Manu Sharma, Claudia Schulte, Margaux F. Keller, Sampath Arepalli, Christopher T. Letson, Connor Edsall, Hreinn Stefánsson, Xinmin Liu, Hannah A. Pliner, Joseph H. Lee, Rong Cheng, M. Arfan Ikram, John P. A. Ioannidis, Georgios M. Hadjigeorgiou, Joshua C. Bis, María Martínez, Joel S. Perlmutter, Alison Goate, Karen Marder, Brian Fiske, Margaret Sutherland, Georgia Xiromerisiou, Richard H. Myers, Lorraine N. Clark, Kári Stéfansson, John Hardy, Peter Heutink, Honglei Chen, Nicholas Wood, Henry Houlden, Haydeh Payami, Alexis Brice, William K. Scott, Thomas Gasser, Lars Bertram, Nicholas Eriksson, Tatiana Foroud, Andrew Singleton,

Genomic variations and chromosomal abnormalities

Andrew Singleton and colleagues report a large-scale meta-analysis of genome-wide association data in Parkinson's disease using over 13,000 cases and 95,000 controls plus additional samples for replication. They identify 6 new risk loci and replicate 28 independent risk variants for Parkinson's disease across 24 loci. 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.