A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci

Abstract

Common variant genome-wide association studies (GWASs) have, to date, identified >24 risk loci for Parkinson's disease (PD). To discover additional loci, we carried out a GWAS comparing 6,476 PD cases with 302,042 controls, followed by a meta-analysis with a recent study of over 13,000 PD cases and 95,000 controls at 9,830 overlapping variants. We then tested 35 loci (P < 1 × 10−6) in a replication cohort of 5,851 cases and 5,866 controls. We identified 17 novel risk loci (P < 5 × 10−8) in a joint analysis of 26,035 cases and 403,190 controls. We used a neurocentric strategy to assign candidate risk genes to the loci. We identified protein-altering or cis–expression quantitative trait locus (cis-eQTL) variants in linkage disequilibrium with the index variant in 29 of the 41 PD loci. These results indicate a key role for autophagy and lysosomal biology in PD risk, and suggest potential new drug targets for PD.

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Figure 1: A flow chart of the two-stage meta-analysis design.
Figure 2: Results of the Parkinson's disease discovery-phase meta-analysis.
Figure 3: The candidate genes for regions associated with Parkinson's disease.

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Acknowledgements

We thank all of the subjects who donated their time and biological samples to be a part of this study. Funding details and additional acknowledgments are provided in Supplementary Note 1.

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D.C., M.A.N., I.B.H., the 23andMe Research Team, G.A.K., B.B., M.S., D.H., T.W.B., A.B.S., T.R.B., and R.R.G. contributed to the study design. D.C., M.A.N., I.B.H., T.R.B., and D.H. contributed to analysis and methods. D.C., M.A.N., T.W.B., A.B.S., T.R.B., and R.R.G. wrote the manuscript. D.C., M.A.N., I.B.H., J.H., M.v.d.B., F.C., the International Parkinson's Disease Genomics Consortium (IPDGC), the 23andMe Research Team, G.A.K., G.A., B.B., M.S., D.H., T.W.B., A.B.S., T.R.B., and R.R.G. reviewed the manuscript. M.v.d.B., F.C., IPDGC and the 23andMe Research Team provided samples or data.

Corresponding author

Correspondence to Robert R Graham.

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Competing interests

D.C., J.H., F.C., G.A.K., G.A., B.B., M.S., T.W.B., T.R.B., and R.R.G. are employees of Genentech, a member of the Roche group. M.v.d.B. was employed by Genentech when the study was carried out. I.B.H. was employed by 23andMe Inc. when the study was carried out. Members of the 23andMe Research Team and D.H. are employees of 23andMe Inc. M.A.N. also consults for Illumina Inc., the Michael J. Fox Foundation, and University of California Healthcare.

Additional information

A list of members appears in Supplementary Note 1.

A list of members appears in Supplementary Note 1.

Supplementary information

Supplementary Text and Figures

Supplementary Note 1, Supplementary Figures 1–7, Supplementary Tables 2, 3, 7, 8, 11 (PDF 4728 kb)

Life Sciences Reporting Summary (PDF 129 kb)

Supplementary Table 1

Enrichment statistics for PD heritability across 24 annotations. (XLSX 53 kb)

Supplementary Table 4

Candidate PD associations with P < 1 × 10−6 in the discovery meta-analysis (XLSX 36 kb)

Supplementary Table 5: NeuroX and joint meta-analysis association statistics for loci with P < 1 × 10−6 in the discovery meta-analysis

Grayed out rows represent weaker proxies that were not included in the main manuscript. No suitable proxies were available for rs62333164 and rs4657041. (XLSX 41 kb)

Supplementary Table 6

Variants with regulomeDB scores > 3 that are in LD with novel PD-associated index SNPs (XLSX 46 kb)

Supplementary Table 9: Cis-eQTLs for PD-associated loci

For PD associated regions with significant cis-eQTLs (as displayed in Figure 3), the brain and nonbrain tissue with the most significant p-value is listed for each PD loci. “Risk expression” considers the direction of expression the risk allele is associated with. (XLSX 44 kb)

Supplementary Table 10

Genes within 250 kb of PD-associated loci with evidence of coexpression and/or protein–protein interactions (XLSX 46 kb)

Supplementary Table 12

General gene-set enrichment analysis of PD associations (XLSX 343 kb)

Supplementary Table 13

All protein-coding genes within 250 kb of PD-associated loci used as input for STRING analysis (XLSX 34 kb)

Supplementary Table 14

Minimum P values for the 42 genes in the lysosomal pathway for which SNPs tested in this meta-analysis were within 250 kb (XLSX 43 kb)

Supplementary Table 15

Minimum P values for 117 genes in the mitochondrial pathway for which SNPs tested in this meta-analysis were within 250 kb. (XLSX 45 kb)

Supplementary Table 16

Minimum P values for 25 genes in the autophagy pathway for which SNPs tested in this meta-analysis were within 250 kb. (XLSX 41 kb)

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Chang, D., Nalls, M., Hallgrímsdóttir, I. et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson's disease risk loci. Nat Genet 49, 1511–1516 (2017). https://doi.org/10.1038/ng.3955

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