Secondary Logo

Journal Logo

New Insights Into Functional Abdominal Pain and Irritable Bowel Syndrome in Children: A Multidisciplinary Approach

Genetics and Functional Bowel Disease

Talley, Nicholas J

Author Information
Journal of Pediatric Gastroenterology and Nutrition: November 2008 - Volume 47 - Issue 5 - p 680–682
doi: 10.1097/01.mpg.0000338957.89673.e8
  • Free

There are thought to be several distinct functional gastrointestinal disorders, but all of them remain largely mysterious in terms of the underlying pathogenesis (1). Several lines of evidence now support the hypothesis that genetic factors and gene–environment interactions are important in the pathogenesis of these disorders.


Both irritable bowel syndrome (IBS) and functional dyspepsia (FD) may cluster in families. Locke et al found an increased risk for subjects with IBS and dyspepsia reporting a first-degree relative with abdominal pain and/or bowel disturbance (2). This did not apply to spousal controls, even adjusting for potential confounders such as age, sex, and somatization, but a limitation was that the results were based on self-report. In IBS, these results were subsequently confirmed by screening the first-degree relatives of IBS cases and spousal controls (3). Familial clustering, however, could be explained by common early environmental factors and/or genetic factors.


One method to dissect genetic from environmental effects is twin studies. A large study from the United Kingdom using the Rome II criteria for IBS failed to identify any increased concordance of IBS in monozygotic (MZ, or genetically identical) twins versus dizygotic twins (sharing half the same genes) (4). Four other twin studies, from Australia (5), the United States (6,7), and Norway (8), have identified an increased concordance for IBS in MZ twins, although the strength of the association has varied. The definitions of IBS used in 3 of these positive studies (5,6,8) were less specific than the Rome II criteria. This may suggest that the specific IBS phenotype described by the Rome criteria does not have a genetic component, but a US twin study applying Rome II criteria supports a genetic contribution (7).

One key advance has been the recent identification of a possible gene–environment interaction. In the Norwegian twin study (8), the presence of restricted fetal growth (<1500 g) was a significant risk factor for the development of IBS, with the onset of IBS appearing a mean of 7.7 years earlier in low birth weight babies. Furthermore, MZ twins with IBS (vs no IBS) had significantly lower birth weights (8). This gene–environment interaction requires confirmation, but it may indicate that impaired maturation of the nervous system interacts with key genes in inducing IBS-like features (9).


Although it is well established that psychiatric diagnoses are more common in patients with IBS (1), whether this is explained by any common genetic or early environmental factors is unknown. One hypothesis is that the genes that predispose to IBS are the same genes that predispose to depression; however, recent work using co-twin analysis (focusing solely on MZ twins) suggests that this is unlikely (10,11).


Single nucleotide polymorphisms are common genetic variations that occur by chance and, if functional, produce human diversity (12). A number of attempts have been made to find an association between functional single nucleotide polymorphisms and IBS or FD that theoretically may be relevant to the pathogenesis. As with many other shotgun-like approaches, the results have been inconclusive. Although some individual studies have suggested that a functional polymorphism for the gene-encoding activity of the serotonin transporter was associated with IBS (12,13), a meta-analysis concluded there was no such association present (14). More excitement has been generated by the finding of a G-protein polymorphism (GNbeta 3) in functional dyspepsia, with the homozygous CC genotype linked to functional dyspepsia in 2 independent studies (15–17). A positive association of IBS and an interleukin-10 polymorphism has also been reported (18), but work with other candidate genes in cytokine or receptor pathways to date has been convincingly negative (12,14).

This does not mean that there may not be important genes that account for some cases of IBS or FD. For example, patients with a mutation in a sodium channel gene (SCN5A) were significantly more likely to report gastrointestinal symptoms, especially abdominal pain, versus those that did not have this mutation, suggesting a possible link (19). The gene association studies have generally been too small, however, and many of the positive results probably reflect type I error, whereas the negative findings may reflect type II error. Furthermore, no genome-wide scans have yet been reported, although the challenges of adequately defining the phenotype remain a key concern.


The field of genetics of functional bowel disorders is in its infancy but remains potentially exciting. There is growing evidence that functional bowel disorders do run in families, and some of this clustering is likely to be genetic or due to gene–environment effects. Applying a broad definition, there is convincing evidence that the concordance of at least IBS is increased in identical twins. Psychiatric comorbidity in IBS does not appear to be explained by a common genetic link. Rigorous and large genetic epidemiology studies are now needed to identify the relevant functional genes. Such research is likely to lead to changes in our current concepts of the phenotype of IBS and FD. The work also has the potential to progress the concept of individualized medicine to our patients living with these common and often debilitating problems.


1. Talley N, Spiller RC. Irritable bowel syndrome: a little understood organic bowel disease? Lancet 2002; 360:555–564.
2. Locke GR III, Zinsmeister AR, Talley NJ, et al. Familial association in adults with functional gastrointestinal disorders. Mayo Clin Proc 2000; 75:907–912.
3. Kalantar JS, Locke GR III, Zinsmeister AR, et al. Familial aggregation of irritable bowel syndrome: a prospective study. Gut 2003; 52:1703–1707.
4. Mohammed I, Cherkas LF, Riley SA, et al. Genetic influences in irritable bowel syndrome: a twin study. Am J Gastroenterol 2005; 100:1340–1344.
5. Morris-Yates A, Talley NJ, Boyce PM, et al. Evidence of a genetic contribution to functional bowel disorder. Am J Gastroenterol 1998; 93:1311–1317.
6. Levy RL, Jones KR, Whitehead WE, et al. Irritable bowel syndrome in twins: heredity and social learning both contribute to etiology. Gastroenterology 2001; 121:799–804.
7. Lembo A, Zaman M, Jones M, et al. Influence of genetics on irritable bowel syndrome, gastro-oesophageal reflux and dyspepsia: a twin study. Aliment Pharmacol Ther 2007; 25:1343–1350.
8. Bengtson MB, Ronning T, Vatn MH, et al. Irritable bowel syndrome in twins: genes and environment. Gut 2006; 55:1754–1759.
9. Talley NJ. Genes and environment in irritable bowel syndrome: one step forward. Gut 2006; 55:1694–1696.
10. Wojczynski MK, North KE, Pedersen NL, et al. Irritable bowel syndrome: a co-twin control analysis. Am J Gastroenterology 2007; 102:2220–2229.
11. Whitehead WE. Twin studies used to prove that the comorbidity of major depressive disorder with IBS is NOT influenced by heredity. Am J Gastroenterology 2007; 102:2230–2231.
12. Saito YA, Petersen GM, Locke GRI, et al. The genetics of irritable bowel syndrome. Clin Gastroenterol Hepatol 2005; 3:1057–1065.
13. Saito YA, Locke GRR, Zimmerman JM, et al. A genetic association study of 5-HTT LPR and GNbeta3 C825T polymorphisms with irritable bowel syndrome. Neurogastroenterol Motil 2007; 19:465–470.
14. Geeraerts B, Van Oudenhove L, Tack J. Serotonin transporter gene polymorphisms in irritable bowel syndrome. Neurogastroenterol Motil 2006; 18:957–959.
15. Holtmann G, Siffert W, Haag S, et al. G-protein beta 3 subunit 825 CC genotype is associated with unexplained (functional) dyspepsia. Gastroenterology 2004; 126:971–979.
16. Camilleri CE, Carlson PJ, Camilleri M, et al. A study of candidate genotypes associated with dyspepsia in a U.S. community. Am J Gastroenterol 2006; 101:581–592.
17. Holtmann G, Talley NJ. Hypothesis driven research and molecular mechanisms in functional dyspepsia: the beginning of a beautiful friendship in research and practice? Am J Gastroenterol 2006; 101:593–595.
18. Gonsalkorale WM, Perrey C, Pravica V, et al. Interleukin 10 genotypes in irritable bowel syndrome: evidence for an inflammatory component? Gut 2003; 52:91–93.
19. Locke GR 3rd, Ackerman MJ, Zinsmeister AR, et al. Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: evidence of an intestinal channelopathy. Am J Gastroenterol 2006; 101:1299–1304.
© 2008 Lippincott Williams & Wilkins, Inc.