Genome-wide Pleiotropy Between Parkinson Disease and Autoimmune Diseases

Abstract

Importance: Recent genome-wide association studies (GWAS) and pathway analyses supported long-standing observations of an association between immune-mediated diseases and Parkinson disease (PD). The post-GWAS era provides an opportunity for cross-phenotype analyses between different complex phenotypes.

Objectives: To test the hypothesis that there are common genetic risk variants conveying risk of both PD and autoimmune diseases (ie, pleiotropy) and to identify new shared genetic variants and their pathways by applying a novel statistical framework in a genome-wide approach.

Design, setting, and participants: Using the conjunction false discovery rate method, this study analyzed GWAS data from a selection of archetypal autoimmune diseases among 138 511 individuals of European ancestry and systemically investigated pleiotropy between PD and type 1 diabetes, Crohn disease, ulcerative colitis, rheumatoid arthritis, celiac disease, psoriasis, and multiple sclerosis. NeuroX data (6927 PD cases and 6108 controls) were used for replication. The study investigated the biological correlation between the top loci through protein-protein interaction and changes in the gene expression and methylation levels. The dates of the analysis were June 10, 2015, to March 4, 2017.

Main outcomes and measures: The primary outcome was a list of novel loci and their pathways involved in PD and autoimmune diseases.

Results: Genome-wide conjunctional analysis identified 17 novel loci at false discovery rate less than 0.05 with overlap between PD and autoimmune diseases, including known PD loci adjacent to GAK, HLA-DRB5, LRRK2, and MAPT for rheumatoid arthritis, ulcerative colitis and Crohn disease. Replication confirmed the involvement of HLA, LRRK2, MAPT, TRIM10, and SETD1A in PD. Among the novel genes discovered, WNT3, KANSL1, CRHR1, BOLA2, and GUCY1A3 are within a protein-protein interaction network with known PD genes. A subset of novel loci was significantly associated with changes in methylation or expression levels of adjacent genes.

Conclusions and relevance: The study findings provide novel mechanistic insights into PD and autoimmune diseases and identify a common genetic pathway between these phenotypes. The results may have implications for future therapeutic trials involving anti-inflammatory agents.

Figure 1.. Pleiotropic Enrichment of Parkinson Disease (PD) Conditioned on Association P Values of Autoimmune Diseases

Conditional quantile-quantile plots (nominal vs empirical –log₁₀ P values) are calculated from single-nucleotide polymorphism (SNP) populations of varying degrees of association with autoimmune diseases. Each population is composed of SNPs that pass certain significance of association (type 1 diabetes [T1D], Crohn disease [CD], ulcerative colitis [UC], rheumatoid arthritis [RA], celiac disease, psoriasis, and multiple sclerosis [MS]) at P ≤ 1 (All SNPs), P < 10⁻¹, P < 10⁻², and P < 10⁻³. All P values have been corrected for genomic inflation. Dotted lines indicate the expected line under the null hypothesis, and leftward deflection shows increasing degrees of enrichment.

Figure 2.. Conjunctional False Discovery Rate Manhattan Plot of − log₁₀ Values for the Associated Autoimmune Phenotypes

All single-nucleotide polymorphisms without pruning are plotted: enlarged points represent significant single-nucleotide polymorphisms with conjunction false discovery rate less than 0.05, and small points represent the nonsignificant single-nucleotide polymorphisms. The most significant single-nucleotide polymorphism in each linkage disequilibrium block is marked with black circles and annotated with its closest gene, showing the localization of 17 common loci (some loci may have multiple genes) between Parkinson disease and autoimmune diseases listed in Table 1. CD indicates Crohn disease; MS, multiple sclerosis; RA, rheumatoid arthritis; T1D, type 1 diabetes; and UC, ulcerative colitis.

Figure 3.. Functional Gene Network for Novel Pleiotropic Loci From the Present Analysis and Previously Confirmed Parkinson Disease

The protein-coding genes closest to the most associated single-nucleotide polymorphism in the pleiotropic loci and the previously confirmed Parkinson disease loci were used to construct a functional similarity network of genes (see the Methods section). Nodes are colored to show association. The thickness of lines connecting nodes indicates the strength of the association between nodes.