Identification of candidate parkinson disease genes by integrating genome-wide association study, expression, and epigenetic data sets

Importance: Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. Design and Setting: This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. Main Outcomes and Measures: It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. Results: Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. Conclusions and Relevance: together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies.Funding/Support: This study was supported by the Medical Research Council and Wellcome Trust Disease Centre (grant WT089698/Z/09/Z to Drs Wood and Hardy). Funding for the project was provided by the Wellcome Trust under awards 076113, 085475, and 090355. This study was also supported by Parkinson’s UK (grants 8047 and J-0804) and the MRC (G0700943 and G1100643). This work was supported by the MRC grant MR/N026004/1. The Braineac project was supported by the MRC through the MRC Sudden Death Brain Bank Grant (MR/G0901254) to Dr Hardy. Dr Lewis was supported by grants MR/N026004/1 and MR/L010933/1 from the MRC and the Michael J. Fox Foundation for Parkinson’s Research. Dr Trabzuni was supported by the King Faisal Specialist Hospital and Research Centre and the Michael J. Fox Foundation for Parkinson’s Research. Dr Hardy was supported by the Dolby Foundation. Dr Ferrari is supported by grant 284 from the Alzheimer’s Society. University College London Hospitals and University College London receive support from the Department of Health’s National Institute for Health Research (NIHR) Biomedical Research Centres (BRC). Dr Wood is an NIHR senior investigator and receives support from the JPND-MRC Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson’s disease (COURAGE). Ms Reynolds is supported through the award of a Leonard Wolfson Doctoral Training Fellowship in Neurodegeneration. This work was supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Environmental Health Sciences, both part of the National Institutes of Health, Department of Health and Human Services; project numbers 1ZIA-NS003154, Z01-AG000949-02, and Z01-ES101986. In addition, this work was supported by the Department of Defense (award W81XWH-09-2-0128), and the Michael J. Fox Foundation for Parkinson’s Research. This work was supported by National Institutes of Health grants R01NS037167, R01CA141668, and P50NS071674; American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and 'nanced by the Forschungszentrum für Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German Federal Ministry of Education and Research (BMBF) under the funding code 031A430A, the EU Joint Programme - Neurodegenerative Diseases Research (JPND) project under the aegis of JPND (www.jpnd.eu) through Germany, BMBF, funding code 01ED1406 and iMed - the Helmholtz Initiative on Personalized Medicine. This study is funded by the German National Foundation grant (DFG SH599/6-1), Michael J Fox Foundation, and MSA Coalition, USA. The French GWAS work was supported by the French National Agency of Research (ANR-08-MNP-012). This study was also funded by France-Parkinson Association, Fondation de France, the French program “Investissements d’avenir” funding (ANR-10-IAIHU-06) and a grant from Assistance Publique-Hôpitaux de Paris (PHRC, AOR-08010) for the French clinical data. This study was also sponsored by the Landspitali University Hospital Research Fund; Icelandic Research Council; and European Community Framework Programme 7, People Programme, and IAPP on novel genetic and phenotypic markers of Parkinson’s disease and Essential Tremor (MarkMD), contract number PIAP-GA-2008-230596 MarkMD. Institutional research funding IUT20-46 was received from the Estonian Ministry of Education and Research. The McGill study was funded by the Michael J. Fox Foundation and the Canadian Consortium on Neurodegeneration in Aging (CCNA). Sequencing and genotyping done in McGill University was supported by grants from the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA) and in part thanks to funding from the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) progra