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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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.

Author information

Author notes

    • Ingileif B Hallgrímsdóttir
    •  & Marcel van der Brug

    Present addresses: Amgen, South San Francisco, California, USA (I.B.H.); E-Scape Bio, South San Francisco, California, USA (M.v.d.B.).

    • Tushar R Bhangale
    •  & Robert R Graham

    These authors contributed equally to this work.

Affiliations

  1. Genentech, Inc., South San Francisco, California, USA.

    • Diana Chang
    • , Julie Hunkapiller
    • , Marcel van der Brug
    • , Fang Cai
    • , Geoffrey A Kerchner
    • , Gai Ayalon
    • , Baris Bingol
    • , Morgan Sheng
    • , Timothy W Behrens
    • , Tushar R Bhangale
    •  & Robert R Graham
  2. Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.

    • Mike A Nalls
    •  & Andrew B Singleton
  3. Data Tecnica International, Glen Echo, Maryland, USA.

    • Mike A Nalls
  4. 23andMe Inc., Mountain View, California, USA.

    • Ingileif B Hallgrímsdóttir
    •  & David Hinds

Consortia

  1. International Parkinson's Disease Genomics Consortium

    A list of members appears in Supplementary Note 1.

  2. 23andMe Research Team

    A list of members appears in Supplementary Note 1.

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Contributions

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.

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.

Corresponding author

Correspondence to Robert R Graham.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Note 1, Supplementary Figures 1–7, Supplementary Tables 2, 3, 7, 8, 11

  2. 2.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    Enrichment statistics for PD heritability across 24 annotations.

  2. 2.

    Supplementary Table 4

    Candidate PD associations with P < 1 × 10−6 in the discovery meta-analysis

  3. 3.

    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.

  4. 4.

    Supplementary Table 6

    Variants with regulomeDB scores > 3 that are in LD with novel PD-associated index SNPs

  5. 5.

    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.

  6. 6.

    Supplementary Table 10

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

  7. 7.

    Supplementary Table 12

    General gene-set enrichment analysis of PD associations

  8. 8.

    Supplementary Table 13

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

  9. 9.

    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

  10. 10.

    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.

  11. 11.

    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.

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DOI

https://doi.org/10.1038/ng.3955

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