Poster Presentation 40th Annual Lorne Genome Conference 2019

Looking for genes where the sun don't shine: the genetics of bowel symptoms and function (#135)

Mauro D'Amato 1 2
  1. Monash University, Melbourne, VICTORIA, Australia
  2. Karolinska Institutet, Stockholm, Sweden

A healthy state of the gastrointestinal (GI) tract is key to human well-being, and alterations of its function(s) and microenvironment are associated with many GI diseases. Even in the absence of organic causes, conditions like the functional gastrointestinal disorders (FGID) affect 1 every 5 people with symptoms including dyspepsia, abdominal pain, constipation and diarrhea, translating into remarkable healthcare costs. Despite this, FGID pathophysiological mechanisms are underinvestigated and poorly understood, which hampers the development of effective treatment strategies.

At least for irritable bowel syndrome (IBS), the prototypic and most common FGID, a hereditary component has been demonstrated in family and twin studies. However, IBS genetic surveys have been mostly underpowered, and no unequivocal risk locus has been identified. We have pioneered IBS genetic research in the last few years, and recently proposed the use of population-based biobanks and cohorts to study its predisposition. This crystallised into the bellygenes initiative we coordinate: a multi-national project (supported by the BBMRI-LPC consortium) that aims to study IBS, bowel symptoms and genotype in a target population exceeding 800,000 Europeans. Through GWAS studies and their meta-analyses, we focus on multiple IBS definitions and relevant endophenotypes spanning questionnaire data, linkage to healthcare records (ICD codes), and clinical material from tertiary neurogastroenterology centres worldwide.

Through these studies we show that 1) rare and common sucrase-isomaltase (SI) variants increase IBS risk because of their reduced carbohydrate digestion capacity; 2) ion channel activity and specific ion channel genes (SCN5A, TRPM8) are important for bowel motility (stool frequency) and IBS characterised by constipation; 3) a locus on chromosome 9q31.2, known to influence age at menarche, is also associated with IBS risk and harder stools in women. These results implicate genetically predisposing pathways that are therapeutically actionable in IBS, thus providing preliminary rationale for patients stratification and additional treatment options.