Genetic approaches to functional gastrointestinal disorders

Abstract

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.

Figure 1

Intermediate phenotype strategy for FGIDs and frequently comorbid disorders. Shown is the progressive deconstruction of clinical, symptom-based syndromes (several examples are shown in the first row) into intermediate phenotypes (examples are shown in each row) all the way down to the genome. For clarity, only a small number of candidate genes are shown. Although the syndrome and the symptoms can only be studied in humans, the neurobiological endophenotypes can be studied both in humans and in animal models. It has been postulated that the correlation between neurobiological endophenotypes and genes is significantly higher than the correlation between clinical syndromes and genes. IC/PBS, interstitial cystitis/painful bladder syndrome; FM, fibromyalgia; PTSD, posttraumatic stress syndrome; DA, dopamine; NE, norepinephrine; E, epinephrine; CRF, corticotropin-releasing factor; COMT, catechol-O-methyltransferase; AR, adrenoreceptor; VGEF, vascular endothelial growth factor; BDNF, brain-derived neurotrophic factor. Mayer EA, Bushnell MC. Functional pain disorders: time for a paradigm shift? In: Mayer EA, Bushnell MC, eds. Functional pain syndromes: presentation and pathophysiology. Seattle, WA: IASP Press, 2009:531–565. This figure has been reproduced with permission of the International Association for the Study of Pain^® (IASP^®). The figure may not be reproduced for any other purpose without permission.

Figure 2

Simplified model for interaction between genes, peripheral and central endophenotypes, and environmental factors resulting in IBS symptoms. Individual genes influence the function of neural networks in the brain and in the enteric nervous system (including closely related gut cells). Alterations in these neural systems result in alterations in central and peripheral systems related to pain perception, autonomic arousal, peristalsis, and secretion. Significant interactions of genetic with epigenetic factors (including microflora environmental stressors) and with the sex of the individual are likely. PFC, prefrontal cortex; OFC, orbitofrontal cortex; BA 25, Brodman area 25; AM, amygdala. TPH2, tryptophan hydroxylase 2. Mayer EA, Bushnell MC. Functional pain disorders: time for a paradigm shift? In: Mayer EA, Bushnell MC, eds. Functional pain syndromes: presentation and pathophysiology. Seattle, WA: IASP Press, 2009:531–565. This figure has been reproduced with permission of the International Association for the Study of Pain^® (IASP^®). The figure may not be reproduced for any other purpose without permission.