Genetics of irritable bowel syndrome: shifting gear via biobank-scale studies

• Published in: Nature reviews. Gastroenterology & hepatology Vol. 19; no. 11; pp. 689 - 702
• Main Authors: Camilleri, Michael, Zhernakova, Alexandra, Bozzarelli, Isotta, D’Amato, Mauro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2022; Nature Publishing Group
• Subjects: 631/208; 692/4020/1503/1502/2071; Biomedicine; Carbohydrates; Environmental factors; Gastric motility; Gastroenterology; Gastrointestinal diseases; Genetic research; Hepatology; Intestine; Irritable bowel syndrome; Medicine; Medicine & Public Health; Neurotransmitters; Pathophysiology; Receptor mechanisms; Review Article
• DOI: 10.1038/s41575-022-00662-2
• ISSN: 1759-5045

The pathophysiology of irritable bowel syndrome (IBS) is multifactorial and probably involves genetic predisposition and the effect of environmental factors. Unlike other gastrointestinal diseases with a heritable component, genetic research in IBS has been scarce and mostly characterized by small underpowered studies, leading to inconclusive results. The availability of genomic and health-related data from large international cohorts and population-based biobanks offers unprecedented opportunities for long-awaited, well-powered genetic studies in IBS. This Review focuses on the latest advances that provide compelling evidence for the importance of genes involved in the digestion of carbohydrates, ion channel function, neurotransmitters and their receptors, neuronal pathways and the control of gut motility. These discoveries have generated novel information that might be further refined for the identification of predisposed individuals and selection of management strategies for patients. This Review presents a conceptual framework, the advantages and potential limitations of modern genetic research in IBS, and a summary of available evidence. Genetic predisposition contributes to disease pathophysiology in irritable bowel syndrome (IBS). This Review provides a comprehensive overview of genetic research in IBS and discusses new concepts in IBS genetics. Key points The pathophysiological mechanisms associated with irritable bowel syndrome (IBS) are only partially understood; this hampers the development of targeted therapeutic strategies. Genetic research can reveal actionable pathways, but findings have generally been scarce in IBS because genetic investigations have been small scale and based on single-gene approaches that have highlighted only a few putative risk genes related to serotonergic mechanisms, carbohydrate digestion or ion channels. Large-scale, biobank-wide genome-wide association studies (GWAS) that focused on IBS and endophenotypic proxies of gut motility have been reported, and have led to the identification of the first set of unequivocal risk loci. These loci contain several genes relevant to pathways and cell types implicated in the central and enteric nervous system activities, neurotransmitter signalling and enteric motor neuron function; these findings offer avenues for testing novel therapeutic strategies. The genetic architecture of IBS identified to date through GWAS often seems to be shared with comorbid mood disorders and anxiety, which is consistent with the reported efficacy of psychotropic and cognitive therapies in IBS. Polygenic scores derived from GWAS data enabled the identification of individuals at increased risk of IBS in the studied cohorts and could be further refined and validated in independent translational studies.