Gastroenterology

Gastroenterology

Volume 138, Issue 4, April 2010, Pages 1276-1285
Gastroenterology

Reviews in Basic and Clinical Gastroenterology
Genetic Approaches to Functional Gastrointestinal Disorders

https://doi.org/10.1053/j.gastro.2010.02.037Get rights and content

Functional gastrointestinal disorders are complex symptom-based disorders without agreed upon biomarkers or pathophysiology. A better understanding of the genetic architecture of these disorders would help to better identify their complex biology and explain the common comorbidity with other disorders of persistent pain, mood, and affect, as well as possibly make it possible to identify subgroups of patients who respond to customized therapies. In contrast to monogenic diseases, polygenic diseases and traits are characterized by the contribution of common variants in a large number of genes, as well as environmental factors, to the vulnerability of an individual. Family and twin studies have clearly established a genetic component in irritable bowel syndrome. Although candidate gene studies have identified a few gene polymorphisms that may be correlated with the syndrome, small sample size, lack of reproducibility in large data sets, and the unreliability of the clinical phenotype require caution when extrapolating to a major role of any of the reported polymorphisms in the pathophysiology of irritable bowel syndrome. Future progress in this area will require better characterization of intermediate phenotypes with large effect size for the clinical phenotype, as well as consideration of gene-gene, environment-gene (epigenetics), and sex-gene interactions, genome-wide association, and whole genome sequencing approaches in large data sets.

Section snippets

Family and Twin Studies

Familial aggregation has been reproducibly shown in several clinic-based studies of patients with IBS (Table 1), while family studies of other FGIDs are lacking. However, clustering of IBS in families does not necessarily implicate a genetic basis, but could also result from environmental exposures shared in a household, including diet or lifestyle behaviors, exposure to adverse life events within the family, learned cognitions about disease and illness behavior, or even shared exposure to

Candidate Gene Studies

Candidate gene studies are studies whereby investigators postulate that a specific gene, and typically a specific functional gene polymorphism that results in alterations in protein function or quantity, may play a role in disease pathophysiology. The most commonly used approach in IBS to date has been to search for correlations of a candidate gene polymorphism with the symptom-based phenotype IBS (Table 3). More recently, a few studies have aimed to identify correlations between gene

Genome-wide Association Studies and Whole Genome Sequencing

More than 100 genome-wide association studies have been conducted for a large number of human diseases, identifying hundreds of polymorphisms with influence on disease vulnerability.32 However, in most of these studies, one or two genes that had already been known were confirmed, while a large number of common gene variants found in these studies are responsible only for a small fraction of the genetic variation that we know from family and twin studies. It is likely that a large number of

Summary and Conclusions

Gene discovery for complex polygenic disorders such as FGIDs remains a priority but represents a vast challenge. The field, in particular the individual candidate gene hunting approach, has been hampered by use of discrete and narrow symptom-based definitions—focusing on one disorder such as IBS—instead of objective biological phenotypes. Future studies seeking to identify causal genetic loci for FGIDs will likely use a combination of approaches, with candidate gene as well as genome-wide

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    Conflicts of interest The authors disclose no conflicts.

    Funding Supported by a grant from the National Institutes of Health (DK76797 to Y.A.S.) and (DK48351, DK64539, and AT002681 to E.A.M.).

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