期刊
JAMA NEUROLOGY
卷 78, 期 4, 页码 464-472出版社
AMER MEDICAL ASSOC
DOI: 10.1001/jamaneurol.2020.5257
关键词
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资金
- Medical Research Council
- Wellcome Trust [WT089698/Z/09/Z, 076113, 085475, 090355]
- Parkinson's UK [8047, J-0804]
- MRC [G0700943, G1100643, MR/N026004/1, MR/L010933/1]
- MRC through the MRC Sudden Death Brain Bank Grant [MR/G0901254]
- Michael J. Fox Foundation
- King Faisal Specialist Hospital and Research Centre
- Dolby Foundation
- Alzheimer's Society [284]
- Department of Health's National Institute for Health Research (NIHR) Biomedical Research Centres (BRC)
- JPND-MRC Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's disease (COURAGE)
- Leonard Wolfson Doctoral Training Fellowship in Neurodegeneration
- National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, Department of Health and Human Services [1ZIA-NS003154, Z01-AG000949-02, Z01-ES101986]
- National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Services [1ZIA-NS003154, Z01-AG000949-02, Z01-ES101986]
- National Institute of Environmental Health Sciences
- Department of Defense [W81XWH-09-2-0128]
- National Institutes of Health [R01NS037167, R01CA141668, P50NS071674]
- American Parkinson Disease Association (APDA)
- Barnes Jewish Hospital Foundation
- Greater St Louis Chapter of the APDA
- Forschungszentrum fur Umwelt und Gesundheit - German Federal Ministry of Education, Science, Research, and Technology
- State of Bavaria
- German Federal Ministry of Education and Research (BMBF) [031A430A]
- EU Joint Programme - Neurodegenerative Diseases Research (JPND) project under the aegis of JPND through Germany, BMBF [01ED1406]
- iMed - the Helmholtz Initiative on Personalized Medicine
- German National Foundation grant (DFG) [SH599/6-1]
- Michael J Fox Foundation
- MSA Coalition, USA
- French National Agency of Research [ANR-08MNP-012]
- France Parkinson Association
- Fondation de France
- French program Investissements d'avenir fund [ANR-10-IAIHU-06]
- Assistance Publique-Hopitaux de Paris (PHRC) [AOR-08010]
- Landspitali University Hospital Research Fund
- Icelandic Research Council
- European Community [PIAPGA-2008-230596]
- Estonian Ministry of Education and Research [IUT20-46]
- Canadian Consortium on Neurodegeneration in Aging (CCNA)
- Canada First Research Excellence Fund (CFREF)
- McGill University
- MRC [G0802462, MR/N008324/1, MR/K01417X/1] Funding Source: UKRI
This study utilized bioinformatic tools Coloc and TWAS to analyze PD GWAS data from 2017, identifying gene expression and splicing mechanisms associated with PD risk, further characterized using cell-type specificity and weighted coexpression networks. Results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies.
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 Itwas 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.
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