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

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

Research output: Contribution to journalArticlepeer-review

1169 Scopus citations

Abstract

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<sup>-16</sup>). We also show six risk loci associated with proximal gene expression or DNA methylation.

Original languageEnglish (US)
Pages (from-to)989-993
Number of pages5
JournalNature Genetics
Volume46
Issue number9
DOIs
StatePublished - Sep 2014

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