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Lessons learned — resolving the enigma of genetic factors in IBS

Key Points

  • Genetic studies in IBS range from family and twin studies to candidate gene approaches and genome-wide association studies

  • Despite enlarged sample sizes, increased statistical power and meta-analyses, positive associations between gene variations and IBS subtypes are still scarce and many have not been reproduced

  • Epigenetic and pharmacogenetic approaches are in their infancy

  • A major pitfall in IBS research is the lack of large homogenized case–control cohorts recruited according to standardized and harmonized criteria

Abstract

IBS is the most prevalent functional gastrointestinal disorder and phenotypically characterized by chronic abdominal discomfort, pain and altered defecation patterns. The pathophysiology of IBS is multifactorial, albeit with a substantial genetic component. To date, studies using various methodologies, ranging from family and twin studies to candidate gene approaches and genome-wide association studies, have identified several genetic variants in the context of IBS. Yet, despite enlarged sample sizes, increased statistical power and meta-analyses in the past 7 years, positive associations are still scarce and/or have not been reproduced. In addition, epigenetic and pharmacogenetic approaches remain in their infancy. A major hurdle is the lack of large homogenized case–control cohorts recruited according to standardized and harmonized criteria. The COST Action BM1106 GENIEUR (GENes in Irritable Bowel Syndrome Research Network EURope) has been established to address these obstacles. In this Review, the (epi)genetic working group of GENIEUR reports on the current state-of-the-art in the field, highlights fundamental flaws and pitfalls in current IBS (epi)genetic research and provides a vision on how to address and improve (epi)genetic approaches in this complex disorder in the future.

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Figure 1: Multiple layers of complexity on environmental and genetic or epigenetic levels contribute to the pathogenesis of IBS and comorbid conditions.
Figure 2: IBS-related pathways, based on genetic and epigenetic findings including potential pharmacogenetic targets.
Figure 3: Future approach in IBS genetics or epigenetics research.

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Acknowledgements

This manuscript has resulted from the collaboration and network activities of the genetics/epigenetics Working Group (WG3) under the frame of the international network GENIEUR (GENes in Irritable Bowel Syndrome Research Network EURope), which is currently funded by the COST (COoperation in Science and Technology) programme (BM1106, www.GENIEUR.eu). We thank A. Farmer, R. Spiller and C. Fischer for fruitful discussion and comments on the manuscript.

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B.N. and M.G. developed the concept, designed, wrote, assembled input data, and edited the manuscript; B.N. and M.M.W. created and revised the figures; A.M., B.N. and L.K.P. summed up the genetics and epigenetics findings in Tables 1 and 2; M.M.W., L.K.P., M.B.B., E.F., G.N., C.A.D., A.M. and J.S. reviewed the literature, selected the data and wrote the manuscript. All authors discussed the results and implications and commented on the manuscript at all stages.

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Correspondence to Beate Niesler.

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Supplementary Table 1

Summary of genetic association data in IBS. (DOC 180 kb)

Supplementary Table 2

Summary of epigenetic data in IBS. (DOC 47 kb)

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Gazouli, M., Wouters, M., Kapur-Pojskić, L. et al. Lessons learned — resolving the enigma of genetic factors in IBS. Nat Rev Gastroenterol Hepatol 13, 77–87 (2016). https://doi.org/10.1038/nrgastro.2015.206

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