Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets
Por:
Kia, DA, Zhang, D, Guelfi, S, Manzoni, C, Hubbard, L, Reynolds, RH, Botia, J, Ryten, M, Ferrari, R, Lewis, PA, Williams, N, Trabzuni, D, Hardy, J, Wood, NW, Clarimón, J., Dols-Icardo O., Kulisevsky J., Pagonabarraga J., United Kingdom Brain, Int Parkinsons Dis Genomics
Publicada:
1 abr 2021
Ahead of Print:
1 feb 2021
Resumen:
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.
Filiaciones:
Kia, DA:
UCL, Dept Mol Neurosci, Inst Neurol, Queen Sq, London WC1N 3BG, England
Zhang, D:
UCL, Dept Mol Neurosci, Inst Neurol, Queen Sq, London WC1N 3BG, England
Guelfi, S:
UCL, Dept Mol Neurosci, Inst Neurol, Queen Sq, London WC1N 3BG, England
Manzoni, C:
UCL, Sch Pharm, Dept Pharmacol, London, England
Hubbard, L:
Cardiff Univ, Sch Med, Div Psychol Med & Clin Neurosci, Cardiff, S Glam, Wales
Reynolds, RH:
UCL, Dept Mol Neurosci, Inst Neurol, Queen Sq, London WC1N 3BG, England
Botia, J:
Univ Murcia, Dept Ingn Informac & Comunicac, Murcia, Spain
Ryten, M:
UCL, Dept Mol Neurosci, Inst Neurol, Queen Sq, London WC1N 3BG, England
Ferrari, R:
UCL, Dept Mol Neurosci, Inst Neurol, Queen Sq, London WC1N 3BG, England
Lewis, PA:
Royal Vet Coll, Dept Comparat Biomed Sci, London, England
Univ Reading, Sch Pharm, Reading, Berks, England
Williams, N:
Cardiff Univ, Sch Med, Div Psychol Med & Clin Neurosci, Cardiff, S Glam, Wales
Trabzuni, D:
UCL, Dept Mol Neurosci, Inst Neurol, Queen Sq, London WC1N 3BG, England
King Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh, Saudi Arabia
Hardy, J:
UCL, Dementia Res Inst, Dept Neurodegenerat Dis & Reta LilaWeston Labs, London, England
Wood, NW:
UCL, Dept Mol Neurosci, Inst Neurol, Queen Sq, London WC1N 3BG, England
Clarimón, J.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Dols-Icardo O.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Kulisevsky J.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
Pagonabarraga J.:
Institut d’Investigació Biomèdica Sant Pau (IIB SANT PAU), Sant Quintí 77-79, 08041 Barcelona, Spain
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