Background & Aims: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants.
Methods: We studied 7,287,191 high-quality single-nucleotide polymorphisms in individuals who self-reported a doctor s diagnosis of IBS (cases; m=9576) compared to the remainder of the cohort (controls; n=336,499) (mean age of study subjects, 40 69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n=249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories, to obtain biological insights from the observed associations.
Results: We identified a genome-wide significant association on chromosome 9q31.2 (SNP rs10512344; P=3.57 10-8), in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P<5.0 10-6). Sex-stratified analyses revealed that the variants at 9q32.1 affect risk of IBS in only women (P=4.29 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P=.015 in the tertiary cohort) and harder stools in women (P=.0012 in the population-based sample). Functional annotation of the 9q32.1 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia.
Conclusions: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q32.1 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS.
Exploring the genetics of irritable bowel syndrome: the ?bellygenes? initiative (project approved by bbmri-lpc)
Irritable bowel syndrome (IBS) affects 15% of people with symptoms including abdominal pain, bloating, constipation and diarrhoea. It is a leading cause of work absenteeism, and consumes 0.5% of healthcare budget. Aetiology is uncertain with genetic factors playing a predisposing role, though no major large-scale effort has been undertaken.
The bbmri-lpc approved bellygenes proposal aims to study IBS in relation to genotype in several large European cohorts, with unprecedented and adequate statistical power. The results of this initiative will contribute to the identification of pathophysiological mechanisms, and hence ultimately provide novel therapeutic targets in IBS. The extent to which IBS affects health-related QoL is similar to ischaemic heart disease, asthma or migraine, and IBS patients would accept a 1% change of dying from a treatment that makes them symptom free.
In Europe, more than 70 million people are affected by IBS symptoms, translating into costs of 40 billion ?/y for clinical management and loss of productivity. Hence, the potential for societal impact of a commensurate action targeting IBS at different levels is extraordinary. The long-term projected outcomes of the bellygenes initiative are thus expected to positively impact the lives of many Europeans. We adopt a case-control design, where genotypes are studied to identify risk genes. IBS patients and controls will be identified using electronic medical records and ICD codes, and questionnaire-based information on self-reported medical conditions. Genomic DNA variants will be compared for their frequencies in cases and controls in order to identify those associated with increased or decreased IBS risk (genome wide association study ? GWAS). ICD-defined prior gastroenteritis will also be studied to include environmental exposure in the assessment of IBS risk. Ad-hoc bioinformatic tools will be used to infer biology from the genetic association data. We request access to data from individuals with ICD10 diagnoses K58, K58.0, K58.9 (including A01-A09 risk modifiers) and/or non-cancer illness code, self-reported condition irritable bowel syndrome for cases, and unaffected controls. Based on current tally from UKBiobank processed records, we expect this to correspond approximately to 7-8000 ICD10 and 12000 self-reported IBS cases, and we request 10x as many non-IBS controls.
|Lead investigator:||Professor Mauro D'Amato|
|Lead institution:||CIC bioGUNE|
|2546||Female-specific Association Between Variants on Chromosome 9 and Self-reported Diagnosis of Irritable Bowel Syndrome||Bonfiglio et al||2018||Gastroenterology (2018)|