Abstract: Since Tysk et al's pioneering analysis of the Swedish twin registry, twin and family studies continue to support a strong genetic basis of the inflammatory bowel diseases. The coefficient of heritability for siblings of inflammatory bowel disease probands is 25 to 42 for Crohn's disease and 4 to 15 for ulcerative colitis. Heritability estimates for Crohn's disease and ulcerative colitis from pooled twin studies are 0.75 and 0.67, respectively. However, this is at odds with the much lower heritability estimates from Genome-Wide Association Studies (GWAS). This “missing heritability” is likely due to shortfalls in both family studies and GWAS. The coefficient of heritability fails to account for familial shared environment. Heritability calculations from twin data are based on Falconer's method, with premises that are increasingly understood to be flawed. GWAS based heritability estimates may underestimate heritability due to incomplete linkage disequilibrium, and because some single nucleotide polypeptides (SNPs) do not reach a level of significance to allow detection. SNPs missed by GWAS include common SNPs with low penetrance and rare SNPs with high penetrance. All methods of heritability estimation regard genetic and environmental variance as separate entities, although it is now understood that there is a complex multidirectional interplay between genetic are environmental factors mediated by the microbiota, the epigenome, and the innate and acquired immune systems. Due to the limitations of heritability estimates, it is unlikely that a true value for heritability will be reached. Further work aimed at quantifying the variance explained across GWAS, epigenome-wide, and microbiota-wide association studies will help to define factors leading to inflammatory bowel disease.
Article first published online 17 April 2015.
*Department of Gastroenterology, Chelsea and Westminster Hospital, London, United Kingdom;
†Organ Center, Hospital of Southern Jutland, Aabenraa, Denmark;
‡Institute of Regional Health Research-Center Sønderjylland, University of Southern Denmark, Odense, Denmark; and
§Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.
Reprints: Hannah Gordon, BA, MBBS, Department of Gastroenterology, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, United Kingdom (e-mail: firstname.lastname@example.org).
Supported in part by an unrestricted grant from the Jesse and Thomas Tam charitable foundation.
The authors have no conflicts of interest to disclose.
Received January 02, 2015
Accepted February 09, 2015