Circadian clock-related genome-wide Mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity

Abstract

Background Circadian rhythm is crucial to the function of the immune system. Disorders of the circadian rhythm can lead to inflammatory diseases such as UC. This Mendelian Randomization (MR) analysis applies genetic tools to represent the aggregated statistical results of exposure to circadian rhythm disorders and UC and its comorbidities, allowing for causal inferences. Methods Summary statistics were conducted on UC and its comorbidities, protein expression quantitative trait loci, DNA methylation and gene expression in individuals of European ancestry (pQTL, mQTL, and eQTL, respectively). Genetic variants located within or near 120 circadian clock-related genes and closely related to circadian rhythm disorders were selected as instrumental variables, and the causal relationships with UC and its comorbidities were estimated through aggregated summary data-based MR (SMR) analysis. Findings Through preliminary SMR analysis, we found a potential causal relationship between circadian clock-related genes and UC and its comorbidities. Our study identified strong evidence of positive correlation of four overlapping genes (CSNK1E, OPRL1, PIWIL2, and RORC) between MWAS and TWAS were identified in UC, three overlapping genes (OPRL1, CHRNB2, and FBXL17) in UC with PSC, and two overlapping genes (ARNTL and USP7) in UC with arthropathy. Interpretations This SMR study demonstrates the causal effect of circadian rhythm disorders in UC and its comorbidities. In addition, our research identified candidate genes which could serve as potential drug targets.