Rome III criteria capture higher irritable bowel syndrome SNP-heritability and highlight a novel genetic link with cardiovascular traits

Background & Aims: Irritable bowel syndrome (IBS) shows genetic predisposition, 
and large-scale genome-wide association studies (GWAS) are emerging, based on 
heterogeneous disease definitions. We aimed at investigating the genetic architecture 
of IBS defined according to gold-standard Rome Criteria.
Methods: We conducted GWAS meta-analyses of Rome III IBS and its subtypes in 
24,735 IBS cases and 77,149 asymptomatic controls from two independent European 
cohorts (UK Biobank and Lifelines). SNP-based heritability (h2
SNP) and genetic 
correlations (rg) with other traits were calculated. IBS risk loci were functionally 
annotated to identify candidate genes. Sensitivity and conditional analyses were 
conducted to assess impact of confounders. Polygenic risk scores (PRS) were 
computed and tested in independent datasets.
Results: Rome III IBS showed significant SNP-heritability (up to 13%) and similar 
genetic architecture across subtypes, including those with manifestations at the 
opposite ends of the symptom spectrum (rg=0.48 between IBS-D and IBS-C). Genetic 
correlations with other traits highlighted commonalities with family history of heart 
disease and hypertension, coronary artery disease, and angina pectoris (rg=0.20–
0.45), among others. Four independent GWAS signals (p<5×10-8) were detected, 
including two novel loci for IBS (rs2035380) and IBS-Mixed (rs2048419) that had been
previously associated with hypertension and coronary artery disease. Functional 
annotation of GWAS risk loci revealed genes implicated in circadian rhythm (BMAL1), 
intestinal barrier (CLDN23), immunomodulation (MFHAS1), and the cAMP pathway 
(ADCY2). PRS allowed the identification of individuals at increased risk of IBS 
(OR=1.34, p=1.1×10-3).
Conclusions: Rome III Criteria capture higher SNP-heritability than previously 
estimated for IBS. The identified link between IBS and cardiovascular traits may 
contribute to the delineation of alternative therapeutic strategies, warranting further 
investigation
Keywords: genome-wide association study; IBS; genetic correlation; CVD.