Genetics of irritable bowel syndrome and associated gastrointestinal symptoms

Abstract: Irritable bowel syndrome (IBS) affects more than one in ten individuals worldwide and is the most common cause of gut illness. It is classified according to the symptom-based Rome criteria as a functional gastrointestinal disorder (FGID) characterized by recurrent abdominal pain or discomfort accompanied with altered bowel habits (diarrhea, constipation or both). Although the research interest in IBS has grown considerably lately and several contributing factors are being recognized, the etiology of IBS is still far from understood. Hence, there is no effective cure and no established biomarkers, and current therapeutic options can only be directed towards symptom amelioration. IBS significantly reduces peoples’ quality of life and working ability, and has important socioeconomic consequences, posing a considerable burden both on the affected individual and the society at large. Therefore, there is an urgent need for improved understanding of this common gastrointestinal disorder. A heritable component in IBS has been demonstrated although inadequately studied; hence not much is known about the specific genetic architecture of IBS. Through focused genetic research, we strive to gain novel insight into the pathophysiology of IBS. Eventually, these studies will contribute to shifting the paradigm from symptom-based definitions to a molecular re-classification of patients, for clinical translation and post‐genomic approaches to stratified medicine in IBS. The overall aim of this thesis was therefore to identify, validate and functionally characterize genetic factors predisposing to IBS and associated gastrointestinal symptoms. The first three papers included in this thesis are hypothesis- or pathway-driven candidate-gene studies investigating the role of specific genes in IBS predisposition, while the fourth paper is an important step in our broader approach to using large general population-based studies for IBS gene-hunting efforts. In paper I, we showed that genetic variation in the NPSR1 gene influences children’s predisposition to recurrent abdominal pain (RAP), the cardinal symptom of IBS and related FGIDs. The NPSR1 gene encodes the neuropeptide S (NPS) receptor, and previous evidence suggests its signaling to influence functions along the brain-gut axis, including mucosal immune activity, secretion of other neuropeptides and gut hormones, pain perception, and gut motor and sensory functions. In paper II we aimed to investigate the role of ion channel genes in IBS risk. By genotyping a Swedish case-control cohort for four genes that showed nominal significance in our previously published pilot genome-wide association study (GWAS) of IBS, we could provide evidence of association for the transient receptor potential cation channel gene TRPM8 (the ‘cold and menthol receptor’). TRPM8 polymorphisms showed significant association with constipation-predominant IBS subtypes (IBS-C/M), and risk alleles further correlated with harder stool consistency in an independent population-based Swedish dataset. In paper III, through a series of experiments and association analyses, we could demonstrate a potential mechanism underlying the often perceived link between carbohydrate consumption and IBS symptoms. Rare sucrase-isomaltase (SI) mutations were more common in IBS patients compared to controls or the general population, and we also provide evidence of a functionally relevant coding SNP that significantly increases the risk of IBS, especially diarrhea-predominant IBS. This study suggests that milder forms of genetically derived SI deficiency may be present in subgroups of patients currently classified as IBS. Finally, paper IV represents an important step in an alternative strategy for the identification of IBS risk genes and variants; a general population-based approach utilizing existing data in large epidemiological cohorts and biobanks. Here we conducted a meta-analysis of a total of 1,335 IBS cases and 9,768 asymptomatic controls from five independent European GWA studies, and although no genome-wide significant association was detected, the results from this study identify seven suggestive IBS risk loci for further investigation and highlight ion channel activity as potentially implicated in IBS pathophysiology. In conclusion, elucidating the genetic architecture of IBS is a truly challenging task, but as we are making progress, the studies in this thesis represent a significant step forward. We provide evidence for the importance of specific genes (NPSR1, TRPM8 and SI) in the development of IBS and associated phenotypes in subsets of patients, contribute to the emerging evidence suggesting a role of ion channels in IBS pathophysiology, and confirm the applicability of using large general-population based cohorts for the discovery of IBS risk genes and variants.