Genetic interactions can help to explain Crohn’s disease heritability and improve risk preciction
Over the past 25 years there have been significant advances in our understanding of the genetic architecture of inflammatory bowel disease (IBD). Collaborative research groups, such as the International IBD Genetics Consortium, have performed largescale appraisals of the genome of individuals with IBD – few other complex diseases have been studied so extensively.1 However, even with the identification of at least 71 trait-associated genetic risk loci, only a small proportion of Crohn’s disease (CD) heritability can be explained.2
The exact cause of Crohn’s disease (CD) is not yet known, but is thought to be the result of an abnormal immune response to intestinal microbiota in genetically-susceptible individuals.1 The genetic contribution to CD risk was first explored by linkage analysis using families, and further progress was made through genome-wide association studies (GWASs).3 GWAS and meta-analyses have identified at least 71 CD-associated genetic risk loci. However, of the estimated heritability determined by studies of twin pairs, only 23% of CD heritability could be explained by the additive effects of the 71 CD risk loci. It has been postulated that genetic interactions may account for some of the missing or ‘hidden’ heritability, and could improve CD risk predictive models that rely on additive genetics alone.2
((callout)) Genetic interactions may inflate CD heritability compared to strictly additive genetics.4
While quantitative geneticists have long known of the impact that genetic interactions may have on heritability calculations, studies of missing heritability have thus far paid little attention to genetic interactions.4 Wang and colleagues conducted the first study to evaluate the predictive value of genetic interactions. High-order interactions between loci were identified using logic regression. Both the cumulative effect of 71 GWAS meta-analysis CD risk loci and the interactions amongst the loci were taken into account when calculating CD heritability. Their case-control study found that genetic interactions increased estimated CD heritability to 27%, and risk prediction was improved from 75% to 77% (p<0.0001). An increase in explained heritability was also observed when the same five genetic interactions were applied to a larger data set (from 21% to 22%). Interestingly, there were only small differences in cumulative allele scores between CD and healthy subjects. This may explain why only 23% of heritability may be attributed to the 71 CD loci. The statistical model that accounts for the interactions between gene variants – rather than the variants alone – is a step towards the full understanding of CD pathogenesis.2
It should be noted that the identification of the genetic contribution to pathogenesis is not necessarily a goal in itself – the priority of IBD research is to improve patient care and treatment.5 Ideally, the identification of IBD’s genetic architecture will ultimately assist in individualising therapy for each patient and predicting response to therapeutic agents.1
- Ventham NT et al. Beyond gene discovery in inflammatory bowel disease: the emerging role of epigenetics. Gastroenterology 2013; 145: 293–308.
- Wang MH et al. A novel approach to detect cumulative genetic effects and genetic interactions in Crohn's disease. Inflamm Bowel Dis 2013 19:1799–1808.
- Elding et al. Refinement in localization and identification of gene regions associated with Crohn disease. Am J Hum Genet 2013; 92: 107–113.
- Zuk O et al. The mystery of missing heritability: Genetic interactions create phantom heritability. Proc Natl Acad Sci 2012; 109: 1193–1198.
- Merrick M et al. Challenges in IBD research: updating the scientific agendas. Inflamm Bowel Dis 2003; 9: 137–153.
AU-REM0196. Date prepared: April 2014.