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 Cheng, International Parkinson's Disease Genomics Consortium (IPDGC), Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI), 23andMe, GenePD, NeuroGenetics Research Consortium (NGRC), Hussman Institute of Human Genomics (HIHG), Ashkenazi Jewish Dataset Investigator, Cohorts for Health and Aging Research in Genetic Epidemiology (CHARGE), North American Brain Expression Consortium (NABEC), United Kingdom Brain Expression Consortium (UKBEC), Greek Parkinson's Disease Consortium, Alzheimer Genetic Analysis Group, M 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

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(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.

Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Manhattan plot of discovery phase meta-analyses.
Figure 2
Figure 2
Forest plots describing cohort level and summary effects of risk profile analyses.

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Source: PubMed

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