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

Nature Reviews Gastroenterology & Hepatology volume 19, pages 689–702 (2022)Cite this article

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Abstract

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.

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.

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Fig. 1: Risk factors, pathophysiological mechanisms and intermediate phenotypes contributing to IBS.
Fig. 2: Pathways that have emerged from candidate gene studies in IBS.
Fig. 3: Conceptual framework for the translation of genetic findings to patient stratification in IBS.

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Acknowledgements

The research time of M.C. for IBS studies is funded by NIH RO1 DK115950. A.Z. is supported by ERC Starting Grant 715772, Netherlands Organization for Scientific Research NWO-VIDI grant 016.178.056, Netherlands Heart Foundation CVON grant 2018-27, and NWO Gravitation grant ExposomeNL 024.004.017. The research of M.D’A. in IBS is supported by the Spanish Ministry of Science and Innovation (MICINN, PID2020-113625RB) and the Spanish Agency for Investigation (AEI, PCI2021-122064-2A) under the umbrella of the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL) and of the ERA-NET Cofund ERA-HDHL (GA no. 696295 of the EU Horizon 2020 Research and Innovation Programme).

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Authors and Affiliations

  1. Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER) and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    Michael Camilleri

  2. Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands

    Alexandra Zhernakova

  3. Gastrointestinal Genetics Lab, CIC bioGUNE - BRTA, Derio, Spain

    Isotta Bozzarelli & Mauro D’Amato

  4. Ikerbasque, Basque Foundation for Science, Bilbao, Spain

    Mauro D’Amato

  5. Department of Medicine and Surgery, LUM University, Casamassima, Italy

    Mauro D’Amato

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  1. Michael Camilleri
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Contributions

All authors researched data for the article. All authors contributed substantially to discussion of the content. M.D’A., M.C. and A.Z. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Mauro D’Amato.

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Competing interests

M.C. has received funding for single-centre pharmacodynamic studies from VANDA Pharmaceuticals and NGM Pharmaceuticals. M.D’A. has received financial support from QOL Medical, in the form of unrestricted research grants. A.Z. and I.B. declare no competing interests.

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Related links

GWAS Catalog: https://www.ebi.ac.uk/gwas/

International Classification of Diseases, Ninth Revision (ICD9): https://www.cdc.gov/nchs/icd/icd9.htm

International Classification of Diseases, Tenth Revision (ICD10): https://www.cdc.gov/nchs/icd/icd10.htm

National Institute for Health and Care Excellence: https://www.nice.org.uk/guidance/cg61

Rome criteria: https://theromefoundation.org/rome-iv/rome-iv-criteria/

Glossary

Dysbiosis

Disruption of the intestinal microbiota homeostasis, determining a reduction in microbial diversity, alterations in the composition and distribution of the autochthon commensals, and changes in metabolic activities.

Genetic architecture

Broadly, the genetic landscape that underlies a phenotypic trait and its variation, characterized by the number of genetic variants that contribute to that phenotype, their effect size and the patterns of interactions. It summarizes the ‘genetics’ behind a trait.

Biobanks

Collections of extensive data from biomedical research linked to study participants, including biospecimens, electronic health-related records, genetic data, imaging, biomarkers and information regarding environment and lifestyle.

Prevalence

The proportion of individuals in a population who have a specific characteristic (typically a disease) at a specific time.

GWAS Catalog

A free online curated collection of human genome-wide association study (GWAS) results representing a collaboration between the European Bioinformatics Institute of the European Molecular Biology Laboratory and the National Human Genome Research Institute; it summarizes significant single-nucleotide polymorphism–trait associations, and sample metadata from each publication (as of 9 July 2022, the catalogue contains 5,848 publications and 398,342 associations).

Polygenic scores

(PGS). Values summarizing the estimated (cumulative) effects of multiple DNA variants in determining the probability of an individual manifesting specific phenotypes or traits. The score is useful for evaluating an individual’s genetic predisposition for a particular trait and can also be used as a predictor relative to the general population (increased or decreased risk of disease, expressed as a polygenic risk score for that disease).

Biomarkers

Characteristics that can be objectively measured and evaluated as indicators of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention (adapted from the definition of the Biomarkers Definitions Working Group).

Omics

A set of scientific disciplines (such as genomics, metagenomics, metabolomics, proteomics and transcriptomics) that exploit large-scale data to characterize and quantify molecular interactions at a global level, whether biochemical, molecular or cellular data, or data from organs or other systems.

Genome-wide significance level

The consensus threshold defining the statistical significance of a reported genome-wide association between a single-nucleotide polymorphism and a given trait. Currently defined as P < 5 × 10−8 (originally based on a Bonferroni correction).

Gene set enrichment analysis

A computational method that, based on existing knowledge, allows the identification of biological pathways, functions and/or disease-related categories that are significantly (P < 0.05) enriched in a specific set of genes compared with a reference panel (most often the whole transcriptome).

Suggestive association

A threshold that, although not reaching genome-wide significance, could be used as evidence of association warranting further investigation and validation in independent datasets (often set at P ≤ 5 × 10−6).

Minor allele

The less common allele for a specific single-nucleotide polymorphism in a given population.

Locus

The specific location of a DNA sequence, gene or genetic marker on a chromosome.

Genetic correlations

Parameters that quantify the proportion of variance that two traits share owing to genetic causes, estimating the degree of pleiotropy (the phenomenon by which a single gene or locus influences the phenotypic appearance of multiple traits, including different diseases) or causal overlap.

Mendelian randomization

An analytical method that uses random segregation of genetic variants as an instrument to emulate a randomized controlled trial, to investigate the putative causal effect of an exposure (using genetic variations strongly associated with it) on an outcome of interest, allowing confounders and reverse causation to be reduced; it can be used to test whether genetic predisposition to a disease (outcome) is mediated via DNA variants (instruments) predisposing to another disease (exposure), and vice versa.

Primary and secondary ICD10 diagnoses

According to the ICD-10-CM Official Guidelines for Coding and Reporting, FY 2021, the principal diagnosis is defined as the condition established to be chiefly responsible for occasioning the admission of the patient to the hospital, whereas other diagnoses are all conditions that coexist at the time of admission, develop subsequently, or affect the treatment received and/or the length of stay.

Linkage disequilibrium

In a given population, the non-random segregation of alleles from different loci, resulting in their combinations (haplotypes) occurring more or less often than expected based merely on their individual allele frequencies (random, independent segregation).

Lead SNP

The marker that gives rise to the strongest association signal at a given genome-wide association study locus.

SNP heritability

The proportion of phenotypic variance of a given trait, which is causally explained by a specific set of single-nucleotide polymorphisms (SNPs).

Functional annotation

The process of collecting and assigning functional information to genomic regions, such as genome-wide association study loci (including gene content, regulatory elements, expression, molecular function, subcellular location, interactions, etc).

Major allele

The more common allele for a specific single-nucleotide polymorphism in a given population.

Promoter

A regulatory element; a sequence of DNA that allows the binding of RNA polymerase and transcription factors responsible for the transcription of the downstream gene, therefore fundamentally contributing to its expression.

Alternative splicing

The post-transcriptional process resulting in different combinations of exons from the same precursor mRNA producing alternative mRNA transcripts; this allows a single gene to code for multiple proteins, often associated with developmental and tissue-specific expression.

Post-translational modifications

All the chemical modifications that take place after the translation of a polypeptide chain (such as the addition of functional groups and/or polypeptides, proteolytic cleavage, glycosylation and phosphorylation), expanding the diversity in structures and functions of proteins.

Exposome

The totality of environmental factors an individual is exposed to over a lifetime, usually considered in relation to health measures.

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Camilleri, M., Zhernakova, A., Bozzarelli, I. et al. Genetics of irritable bowel syndrome: shifting gear via biobank-scale studies. Nat Rev Gastroenterol Hepatol 19, 689–702 (2022). https://doi.org/10.1038/s41575-022-00662-2

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