Genetic comorbidities in Parkinson's disease

Abstract

Parkinson's disease (PD) has a number of known genetic risk factors. Clinical and epidemiological studies have suggested the existence of intermediate factors that may be associated with additional risk of PD. We construct genetic risk profiles for additional epidemiological and clinical factors using known genome-wide association studies (GWAS) loci related to these specific phenotypes to estimate genetic comorbidity in a systematic review. We identify genetic risk profiles based on GWAS variants associated with schizophrenia and Crohn's disease as significantly associated with risk of PD. Conditional analyses adjusting for SNPs near loci associated with PD and schizophrenia or PD and Crohn's disease suggest that spatially overlapping loci associated with schizophrenia and PD account for most of the shared comorbidity, while variation outside of known proximal loci shared by PD and Crohn's disease accounts for their shared genetic comorbidity. We examine brain methylation and expression signatures proximal to schizophrenia and Crohn's disease loci to infer functional changes in the brain associated with the variants contributing to genetic comorbidity. We compare our results with a systematic review of epidemiological literature, while the findings are dissimilar to a degree; marginal genetic associations corroborate the directionality of associations across genetic and epidemiological data. We show a strong genetically defined level of comorbidity between PD and Crohn's disease as well as between PD and schizophrenia, with likely functional consequences of associated variants occurring in brain.

Figure 1.

Forest plots from random effects meta-analyses of profiled phenotypes. Cohort-specific OR associated with PD are shown in blue, the size of the square is proportional to the size of the study. Confidence intervals of the summary OR per phenotype are shown as red diamonds, with the centerline of each diamond representing the summary OR for that particular phenotype. The dependent variable in each model is the standardized count of disease risk or quantitative measure increasing alleles per sample associated with either disease status or continuous measures of interest. Abbreviations include Bipolar for bipolar disorder, IBD for inflammatory bowel disease, T2DM for type 2 diabetes, Crohn's for Crohn's disease, UC for ulcerative colitis, Parkinson's for Parkinson's disease, Rheumatoid for Rheumatoid arthritis, Smoking for smoking history/rate, Caffeine for caffeine or coffee consumption levels, amyloid for serum amyloid levels, iron for serum iron levels and urate for serum urate levels.