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

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.

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

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Acknowledgements

We would like to thank all of the subjects who donated their time and biological samples to be a part of this study. For funding details and additional acknowledgments, please see the Supplementary Note.

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Overall study design: M.A.N., N.P., J.B., A.L.D., B.F., M. Sutherland, J.A.H., N.W.W., T.G., W.K.S., L.B., N.E., T.F. and A.B.S. Design and/or management of the individual studies: M.A.N., C.B.D., J.B., C.S., X.L., J.H.L., R.C., G.M.H., J.S.P., A.G., K.M., A.L.D., R.H.M., L.N.C., J.A.H., P.H., H.C., M. Saad, M. Sharma, M. Sutherland, M.A.I., J.C.B., N.W.W., H.H., H. Payami, H.S., K.S., A.B., W.K.S., T.G., N.E., T.F. and A.B.S. Genotyping: D.G.H., E.K., S.A., C.L., C.E. and H. Pilner. Phenotyping: T.F., G.M.H., J.S.P., K.M., G.X., H.C., N.W.W., H.H., H.S., K.S., A.B., T.F. and W.K.S. Statistical methods and data analysis: M.A.N., N.P., C.M.L., D.G.H., E.K., M. Saad, M. Sharma, C.S., J.P.A.I., M.F.K., M.M., A.L.D., W.K.S., L.B., N.E., T.F. and A.B.S. Writing group: M.A.N., N.P., C.M.L., T.F. and A.B.S. Critical review of the manuscript: M.A.N., N.P., C.M.L., C.B.D., D.G.H., E.K., J.B., C.S., M.F.K., G.M.H., M.M., A.G., B.F., M. Saad, M. Sharma, M. Sutherland, G.X., R.H.M., L.N.C., J.A.H., P.H., H.C., N.W.W., H.H., H. Payami, H. Pilner, H.S., K.S., A.B., W.K.S., T.G., L.B., N.E., T.F., A.B.S. and J.S.P.

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Correspondence to Andrew B Singleton.

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The authors declare no competing financial interests.

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A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

A full list of members and affiliations appears in the Supplementary Note.

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Supplementary Note, Supplementary Tables 1–6 and Supplementary Figures 1–5. (PDF 22689 kb)

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Nalls, M., Pankratz, N., Lill, C. et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease. Nat Genet 46, 989–993 (2014). https://doi.org/10.1038/ng.3043

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