Author:
Kia Demis A.,Zhang David,Guelfi Sebastian,Manzoni Claudia,Hubbard Leon,Reynolds Regina H.,Botía Juan,Ryten Mina,Ferrari Raffaele,Lewis Patrick A.,Williams Nigel,Trabzuni Daniah,Hardy John,Wood Nicholas W., ,
Abstract
AbstractSubstantial genome-wide association study (GWAS) work in Parkinson’s disease (PD) has led to an increasing number of loci shown reliably and robustly to be associated with the increased risk of the disease. Prioritising causative genes and pathways from these studies has proven problematic. Here, we present a comprehensive analysis of PD GWAS data with expression and methylation quantitative trait loci (eQTL/mQTL) using Colocalisation analysis (Coloc) and transcriptome-wide association analysis (TWAS) to uncover putative gene expression and splicing mechanisms driving PD GWAS signals. Candidate genes were further characterised by determining cell-type specificity, weighted gene co-expression (WGNCA) and protein-protein interaction (PPI) networks.Gene-level analysis of expression revealed 5 genes (WDR6, CD38, GPNMB, RAB29, TMEM163) that replicated using both Coloc and TWAS analyses in both GTEx and Braineac expression datasets. A further 6 genes (ZRANB3, PCGF3, NEK1, NUPL2, GALC, CTSB) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell-types compared to neurons. The WGNCA analysis showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes related with protein ubiquitination (protein ubiquitination (p=7.47e-10) and ubiquitin-dependent protein catabolic process (p = 2.57e-17) in nucleus accumbens, caudate and putamen, while TMEM163 and ZRANB3 were both important in modules indicating regulation of signalling (p=1.33e-65] and cell communication (p=7.55e-35) in the frontal cortex and caudate respectively. PPI 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. The proteins core proteins this network were enriched for regulation of the ERBB receptor tyrosine protein kinase signalling pathways.Together, these results point to a number of candidate genes and pathways that are driving the associations observed in PD GWAS studies.
Publisher
Cold Spring Harbor Laboratory
Reference39 articles.
1. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial;The Lancet,2017
2. Barbeira A , Dickinson SP , Torres JM , Bonazzola R , Zheng J , Torstenson ES , et al. Integrating tissue specific mechanisms into GWAS summary results. bioRxiv 2017.
3. Insights from cerebellar transcriptomic analysis into the pathogenesis of ataxia;JAMA Neurology,2014
4. An additional k-means clustering step improves the biological features of WGCNA gene co-expression networks;BMC Systems Biology,2017
Cited by
8 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献