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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Corti, O., Lesage, S. & Brice, A. What genetics tells us about the causes and mechanisms of Parkinson's disease. Physiol. Rev. 91, 1161–1218 (2011).
Verstraeten, A., Theuns, J. & Van Broeckhoven, C. Progress in unraveling the genetic etiology of Parkinson disease in a genomic era. Trends Genet. 31, 140–149 (2015).
Nussbaum, R.L. & Ellis, C.E. Alzheimer's disease and Parkinson's disease. N. Engl. J. Med. 348, 1356–1364 (2003).
Shulman, J.M., De Jager, P.L. & Feany, M.B. Parkinson's disease: genetics and pathogenesis. Annu. Rev. Pathol. 6, 193–222 (2011).
Klein, C. & Westenberger, A. Genetics of Parkinson's disease. Cold Spring Harb. Perspect. Med. 2, a008888 (2012).
Hardy, J. Genetic analysis of pathways to Parkinson disease. Neuron 68, 201–206 (2010).
Singleton, A.B., Farrer, M.J. & Bonifati, V. The genetics of Parkinson's disease: progress and therapeutic implications. Mov. Disord. 28, 14–23 (2013).
Nalls, M.A. 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).
Keller, M.F. et al. Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease. Hum. Mol. Genet. 21, 4996–5009 (2012).
Do, C.B. et al. Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease. PLoS Genet. 7, e1002141 (2011).
Fuchsberger, C., Abecasis, G.R. & Hinds, D.A. minimac2: faster genotype imputation. Bioinformatics 31, 782–784 (2015).
Abecasis, G.R. et al. An integrated map of genetic variation from 1,092 human genomes. Nature 491, 56–65 (2012).
Gagliano, S.A. et al. Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases. Ann. Clin. Transl. Neurol. 3, 924–933 (2016).
Willer, C.J., Li, Y. & Abecasis, G.R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 2190–2191 (2010).
Welter, D. et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. 42, D1001–D1006 (2014).
Pickrell, J.K. et al. Detection and interpretation of shared genetic influences on 42 human traits. Nat. Genet. 48, 709–717 (2016).
Nalls, M.A. et al. NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases. Neurobiol. Aging 36, 1605.e7–1605.e12 (2015).
Nalls, M.A. et al. Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies. Lancet 377, 641–649 (2011).
International Parkinson's Disease Genomics Consortium & Wellcome Trust Case Control Consortium 2. A two-stage meta-analysis identifies several new loci for Parkinson's disease. PLoS Genet. 7, e1002142 (2011).
Pankratz, N. et al. Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2. Ann. Neurol. 71, 370–384 (2012).
Wissemann, W.T. et al. Association of Parkinson disease with structural and regulatory variants in the HLA region. Am. J. Hum. Genet. 93, 984–993 (2013).
Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016).
Kichaev, G. et al. Integrating functional data to prioritize causal variants in statistical fine-mapping studies. PLoS Genet. 10, e1004722 (2014).
Maller, J.B. et al. Bayesian refinement of association signals for 14 loci in 3 common diseases. Nat. Genet. 44, 1294–1301 (2012).
Chen, W. et al. Fine mapping causal variants with an approximate Bayesian method using marginal test statistics. Genetics 200, 719–736 (2015).
Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).
Bentham, J. et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat. Genet. 47, 1457–1464 (2015).
GTEx Consortium. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).
Zhang, Y. et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J. Neurosci. 34, 11929–11947 (2014).
Giambartolomei, C. et al. Bayesian test for colocalisation between pairs of genetic association studies using summary statistics. PLoS Genet. 10, e1004383 (2014).
Sidransky, E. et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N. Engl. J. Med. 361, 1651–1661 (2009).
Cang, C., Aranda, K., Seo, Y.J., Gasnier, B. & Ren, D. TMEM175 is an organelle K+ channel regulating lysosomal function. Cell 162, 1101–1112 (2015).
Felbor, U. et al. Neuronal loss and brain atrophy in mice lacking cathepsins B and L. Proc. Natl. Acad. Sci. USA 99, 7883–7888 (2002).
McGlinchey, R.P. & Lee, J.C. Cysteine cathepsins are essential in lysosomal degradation of α-synuclein. Proc. Natl. Acad. Sci. USA 112, 9322–9327 (2015).
Hale, C.M. et al. Identification of modulators of autophagic flux in an image-based high content siRNA screen. Autophagy 12, 713–726 (2016).
Lee, P.H., O'Dushlaine, C., Thomas, B. & Purcell, S.M. INRICH: interval-based enrichment analysis for genome-wide association studies. Bioinformatics 28, 1797–1799 (2012).
Arranz, A.M. et al. LRRK2 functions in synaptic vesicle endocytosis through a kinase-dependent mechanism. J. Cell Sci. 128, 541–552 (2015).
Shin, D., Shin, J.Y., McManus, M.T., Ptácek, L.J. & Fu, Y.H. Dicer ablation in oligodendrocytes provokes neuronal impairment in mice. Ann. Neurol. 66, 843–857 (2009).
Tan, N.N. et al. Epigenetic downregulation of Scn3a expression by valproate: a possible role in its anticonvulsant activity. Mol. Neurobiol. 54, 2831–2842 (2016).
Dittmer, S. et al. TOX3 is a neuronal survival factor that induces transcription depending on the presence of CITED1 or phosphorylated CREB in the transcriptionally active complex. J. Cell Sci. 124, 252–260 (2011).
Kondo, M. et al. SATB1 plays a critical role in establishment of immune tolerance. J. Immunol. 196, 563–572 (2016).
Hopkins, A.L. & Groom, C.R. The druggable genome. Nat. Rev. Drug Discov. 1, 727–730 (2002).
Louis, A.G., Yel, L., Cao, J.N., Agrawal, S. & Gupta, S. Common variable immunodeficiency associated with microdeletion of chromosome 1q42.1-q42.3 and inositol 1,4,5-trisphosphate kinase B (ITPKB) deficiency. Clin. Transl. Immunology 5, e59 (2016).
Wang, Y. et al. Whole-genome association study identifies STK39 as a hypertension susceptibility gene. Proc. Natl. Acad. Sci. USA 106, 226–231 (2009).
Durand, E.Y., Do, C.B., Mountain, J.L. & Macpherson, J.M. Ancestry composition: a novel, efficient pipeline for ancestry deconvolution. bioRxiv Preprint at http://www.biorxiv.org/content/early/2014/10/18/010512 (2014).
Henn, B.M. et al. Cryptic distant relatives are common in both isolated and cosmopolitan genetic samples. PLoS One 7, e34267 (2012).
Howie, B., Fuchsberger, C., Stephens, M., Marchini, J. & Abecasis, G.R. Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat. Genet. 44, 955–959 (2012).
de Bakker, P.I. et al. Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum. Mol. Genet. 17, R122–R128 (2008).
Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).
Bulik-Sullivan, B.K. et al. LD score regression distinguishes confounding from polygenicity in genome-wide association studies. Nat. Genet. 47, 291–295 (2015).
Finucane, H.K. et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nat. Genet. 47, 1228–1235 (2015).
Lee, S.H., Yang, J., Goddard, M.E., Visscher, P.M. & Wray, N.R. Estimation of pleiotropy between complex diseases using single-nucleotide polymorphism-derived genomic relationships and restricted maximum likelihood. Bioinformatics 28, 2540–2542 (2012).
Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6, 80–92 (2012).
dos Santos, G. et al. FlyBase: introduction of the Drosophila melanogaster Release 6 reference genome assembly and large-scale migration of genome annotations. Nucleic Acids Res. 43, D690–D697 (2015).
Eppig, J.T., Blake, J.A., Bult, C.J., Kadin, J.A. & Richardson, J.E. The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease. Nucleic Acids Res. 43, D726–D736 (2015).
McKusick, V.A. MENDELIAN Inheritance in Man and its online version, OMIM. Am. J. Hum. Genet. 80, 588–604 (2007).
Szklarczyk, D. et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 45, D362–D368 (2017).
Smith, A.C. & Robinson, A.J. MitoMiner v3.1, an update on the mitochondrial proteomics database. Nucleic Acids Res. 44, D1258–D1261 (2016).
Calvo, S.E., Clauser, K.R. & Mootha, V.K. MitoCarta2.0: an updated inventory of mammalian mitochondrial proteins. Nucleic Acids Res. 44, D1251–D1257 (2016).
Pagliarini, D.J. et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112–123 (2008).
Brozzi, A., Urbanelli, L., Germain, P.L., Magini, A. & Emiliani, C. hLGDB: a database of human lysosomal genes and their regulation. Database (Oxford) 2013, bat024 (2013).
Moussay, E. et al. The acquisition of resistance to TNFα in breast cancer cells is associated with constitutive activation of autophagy as revealed by a transcriptome analysis using a custom microarray. Autophagy 7, 760–770 (2011).
Kanehisa, M. & Goto, S. KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res. 28, 27–30 (2000).
Gene Ontology Consortium. Gene Ontology Consortium: going forward. Nucleic Acids Res. 43, D1049–D1056 (2015).
Chang, C.C. et al. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7 (2015).
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.
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.
Supplementary Note 1, Supplementary Figures 1–7, Supplementary Tables 2, 3, 7, 8, 11 (PDF 4728 kb)
Enrichment statistics for PD heritability across 24 annotations. (XLSX 53 kb)
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)
Variants with regulomeDB scores > 3 that are in LD with novel PD-associated index SNPs (XLSX 46 kb)
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)
Genes within 250 kb of PD-associated loci with evidence of coexpression and/or protein–protein interactions (XLSX 46 kb)
General gene-set enrichment analysis of PD associations (XLSX 343 kb)
All protein-coding genes within 250 kb of PD-associated loci used as input for STRING analysis (XLSX 34 kb)
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)
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)
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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