Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

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dc.contributor.authorNalls, M.A.
dc.contributor.authorBlauwendraat, C.
dc.contributor.authorVallerga, C.L.
dc.contributor.authorHeilbron, K.
dc.contributor.authorBanders-Ciga, S.
dc.contributor.authorChang, D.
dc.contributor.authoret al
dc.contributor.authorSingleton, A.B.
dc.contributor.author23andME Research Team
dc.contributor.authorSystem Genomics of Parkinson's Disease Consortium
dc.contributor.authorInternational Parkinson's Disease Genomics Consortium
dc.date.accessioned2022-10-12T07:49:41Z
dc.date.available2022-10-12T07:49:41Z
dc.date.issued2019
dc.descriptionScholarly articleen_US
dc.description.abstractBackground: Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods: We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings: Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10-7). Interpretation: These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data.en_US
dc.description.sponsorshipThe National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundationen_US
dc.identifier.citationNalls, M. A., Blauwendraat, C., Vallerga, C. L., Heilbron, K., Bandres-Ciga, S., Chang, D., Tan, M., Kia, D. A., Noyce, A. J., Xue, A., Bras, J., Young, E., von Coelln, R., Simón-Sánchez, J., Schulte, C., Sharma, M., Krohn, L., Pihlstrøm, L., Siitonen, A., Iwaki, H., … International Parkinson's Disease Genomics Consortium (2019). Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies. The Lancet. Neurology, 18(12), 1091–1102. https://doi.org/10.1016/S1474-4422(19)30320-5en_US
dc.identifier.other10.1016/S1474-4422(19)30320-5.
dc.identifier.urihttps://ir.unilag.edu.ng/handle/123456789/11729
dc.language.isoenen_US
dc.publisherElsevieren_US
dc.subjectphenotypesen_US
dc.subjectParkinson's diseaseen_US
dc.subjectDisease risken_US
dc.subjectResearch Subject Categories::MEDICINEen_US
dc.titleIdentification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studiesen_US
dc.typeArticleen_US
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