Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets

Abstract

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.

Figure 1.. Cell-Type–Specific Expression of Coloc-Prioritized Genes in Human and Mouse, and Using Genotype-Tissue Expression (GTEx) Consortium and United Kingdom Brain Expression Consortium (UKBEC) Data

These results illustrate the overrepresentation of glial cell types compared with neuronal cell types among the candidate genes. NA indicates not applicable.

Figure 2.. Literature-Derived Protein-Protein Interaction (PPI) Network

A, Weighted protein-protein interaction network analysis (WPPINA) network visualization of the PPIs specific for the proteins (seeds) coded by the Coloc genes (green nodes). Minor protein interaction partners are shown in blue, while mendelian Parkinson and parkinsonism proteins interacting with parts of the seeds’ interactome are reported in pink. Major interaction partners (ie, they bridge interaction between at least a Coloc protein and a mendelian protein) are labeled in gray. B, The negative control protein network has been randomly sampled to generate 1000 random networks with similar features to the actual Coloc network. These therefore included same or similar number of seeds (9 seeds) to the Coloc protein network and were matched to the mendelian protein network to quantify the number of mendelian proteins able to interact with the random seeds’ interactome. C, Nodes highlighted in yellow (Coloc proteins connected to mendelian Parkinson disease (PD) proteins and internodes) were used to run functional enrichment. The most specific terms of enrichment are reported in the table with their adjusted P value, gene ontology (GO) term identifier, and name. The proteins associated with the enrichment of the terms reported in tables are circled in red.