Gordon Hannah, Trier Moller Frederik, Andersen Vibeke, Harbord Marcus
*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.
Inflamm Bowel Dis. 2015 Jun;21(6):1428-34. doi: 10.1097/MIB.0000000000000393.
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.
自蒂斯克等人对瑞典双胞胎登记处进行开创性分析以来，双胞胎和家族研究持续支持炎症性肠病存在强大的遗传基础。炎症性肠病先证者的兄弟姐妹中，克罗恩病的遗传系数为25至42，溃疡性结肠炎的遗传系数为4至15。汇总双胞胎研究中克罗恩病和溃疡性结肠炎的遗传率估计值分别为0.75和0.67。然而，这与全基因组关联研究（GWAS）得出的低得多的遗传率估计值不一致。这种“遗传率缺失”可能是由于家族研究和GWAS都存在不足。遗传系数未能考虑家族共享环境。根据双胞胎数据进行的遗传率计算基于法尔科纳方法，其前提条件越来越被认为存在缺陷。基于GWAS的遗传率估计可能会低估遗传率，原因是连锁不平衡不完全，以及一些单核苷酸多态性（SNP）未达到可检测的显著水平。GWAS遗漏的SNP包括低外显率的常见SNP和高外显率的罕见SNP。所有遗传率估计方法都将遗传和环境方差视为独立的实体，尽管现在人们认识到，在由微生物群、表观基因组以及先天和后天免疫系统介导的遗传和环境因素之间存在复杂的多向相互作用。由于遗传率估计存在局限性，不太可能得出遗传率的真实值。旨在量化全基因组关联研究、表观基因组范围和微生物群范围关联研究中所解释的方差的进一步工作，将有助于确定导致炎症性肠病的因素。
