Investigating the Genetic Basis of the Co-occurrence of Irritable Bowel Syndrome and Anxiety

Abstract

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder representing a serious burden to the healthcare system. IBS research is extremely challenging due to the multifactorial etiology of the disease and the heterogeneity of patients that present high comorbidity rates with mental disorders including anxiety and depression. Such highly comorbid disorders show substantial heritability and are partly determined by a genetic component. In the present study, we used data available from large pre-existing genome-wide association studies on IBS (n=455,321) and anxiety (n=117,751) to assess the genetic overlap and causal relationship between these comorbid disorders and found strong and positive genetic correlation between them (rg=0.713, se= 0.076, P= 3.6e-20). The multi-trait analysis of GWAS (MTAG) highlighted three new genome-wide significant loci for IBS located in, or nearby, genes related to synaptic transmission, nervous system development, neuroticism, and epigenetic modification of chromatin. We also used Mendelian randomization with a range of sensitivity analyses to clarify the causal relationship between these disorders and found consistent evidence for a causal effect of the genetic liability of IBS on anxiety (P=7.6e-05) but no evidence of causal effect was detected in the opposite direction. Our results are consistent with a shared common genetic background between IBS and anxiety, highlight the importance of common genetic factors in the risk of these comorbid disorders, and add insight into the relationship between gastrointestinal and mental illnesses.