Identification and functional characterization of irritable bowel syndrome (IBS) risk genes and variants

Sammanfattning: As one of the most prevalent functional gastrointestinal disorders (FGIDs), irritable bowel syndrome (IBS) affects more than 10% of the general population worldwide with a higher prevalence in women. The primary clinical manifestation of IBS is chronic abdominal pain or discomfort associated with changes in stool frequency and appearance. IBS is the second leading cause of work absenteeism after colds and has remarkable effects on the socioeconomic system. The pathophysiology of IBS has not been fully clarified yet, including various peripheral and central mechanisms. From the late 1980s, genetic predisposition to IBS has been demonstrated by family and twin studies. Several candidate genes have been linked to IBS susceptibility including TNFSF15, NPSR1, SCN5A, TRPM8, and SI. Moreover, a few underpowered genome-wide association studies (GWAS) have been performed to investigate IBS genetics in population-based cohorts. However, to date, no unequivocal genetic factor has been confirmed yet. In this thesis, we aim to identify risk genes and variants associated with IBS and to characterize their functional roles. The first part focuses on the role of genetic variations in the sucrase-isomaltase (SI) gene and IBS susceptibility. In the second part, the hypothesisfree GWAS approaches are implemented to detect IBS risk genes and variants in large-scale powered cohorts. In Paper I, we have exploited a two-step computational strategy to study the prevalence of SI rare pathogenic variants (SI-RPVs) in 2207 tertiary IBS patients. The prevalence of selected SI-RPVs in all IBS patients is 3.99%, which is significantly higher than the reference population (P=0.00049). This study has provided supporting evidence that links carrying SIRPVs to increased risk of IBS. Paper II has investigated the effects of SI functional variants in the response to dietary intervention in IBS patients. The genotypes of SI hypomorphic variants were obtained for a group of IBS-D patients previously treated with a low FODMAP diet in a clinical trial. After stratifying IBS patients into carriers and non-carriers of SI hypomorphic variants, we have observed significantly lower efficiency of low FODMAP diet in carriers compared to noncarriers (P=0.031). These findings suggest that SI genotype data may contribute to identifying individuals with higher chances to benefit from such dietary interventions. In Paper III, we have performed a GWAS of self-reported IBS exploiting the large population-based UK Biobank. After quality control, the association analysis has been carried out in 9,576 IBS patients and 336,499 controls via logistic regression. Genome-wide significant signals have been identified on chromosome 9q31.2, and sex-stratified analysis suggests this locus is female-specific. This finding has been further supported by replication evidence from analyses in a pooled cohort with multi-national tertiary IBS cases and controls and a Swedish population-based cohort. In the end, IBS GWAS and their meta-analyses have been performed in large-scale multinational tertiary IBS cases and controls from European countries and the US in Paper IV. We have identified two novel genome-wide significant loci in IBS-D meta-analyses, and the results from functional annotation and PheWAS screening have suggested the association of these loci with altered metabolic and immune activities as well as psychiatric conditions. Ion channel biology was also highlighted as plausible pathways linked to IBS. Taken together, this thesis has provided new insight that improves current understanding of genetic predisposition to IBS. In the long run, the discovery of IBS predisposing genes and variants may have a significant impact on IBS management, since it is expected to allow patients stratification and therefore increase the specificity and efficacy of treatment.