Ellinghaus David, Jostins Luke, Spain Sarah L, Cortes Adrian, Bethune Jörn, Han Buhm, Park Yu Rang, Raychaudhuri Soumya, Pouget Jennie G, Hübenthal Matthias, Folseraas Trine, Wang Yunpeng, Esko Tonu, Metspalu Andres, Westra Harm-Jan, Franke Lude, Pers Tune H, Weersma Rinse K, Collij Valerie, D'Amato Mauro, Halfvarson Jonas, Jensen Anders Boeck, Lieb Wolfgang, Degenhardt Franziska, Forstner Andreas J, Hofmann Andrea, Schreiber Stefan, Mrowietz Ulrich, Juran Brian D, Lazaridis Konstantinos N, Brunak Søren, Dale Anders M, Trembath Richard C, Weidinger Stephan, Weichenthal Michael, Ellinghaus Eva, Elder James T, Barker Jonathan N W N, Andreassen Ole A, McGovern Dermot P, Karlsen Tom H, Barrett Jeffrey C, Parkes Miles, Brown Matthew A, Franke Andre
Institute of Clinical Molecular Biology, Christian Albrechts University of Kiel, Kiel, Germany.
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Nat Genet. 2016 May;48(5):510-8. doi: 10.1038/ng.3528. Epub 2016 Mar 14.
We simultaneously investigated the genetic landscape of ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis and ulcerative colitis to investigate pleiotropy and the relationship between these clinically related diseases. Using high-density genotype data from more than 86,000 individuals of European ancestry, we identified 244 independent multidisease signals, including 27 new genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multidisease signals with expression data sets from human, rat and mouse together with epigenetic and expressed enhancer profiles. The comorbidities among the five immune diseases were best explained by biological pleiotropy rather than heterogeneity (a subgroup of cases genetically identical to those with another disease, possibly owing to diagnostic misclassification, molecular subtypes or excessive comorbidity). In particular, the strong comorbidity between primary sclerosing cholangitis and inflammatory bowel disease is likely the result of a unique disease, which is genetically distinct from classical inflammatory bowel disease phenotypes.
我们同时研究了强直性脊柱炎、克罗恩病、银屑病、原发性硬化性胆管炎和溃疡性结肠炎的遗传图谱，以探究多效性以及这些临床相关疾病之间的关系。利用来自86000多名欧洲血统个体的高密度基因型数据，我们确定了244个独立的多疾病信号，包括27个新的全基因组显著易感位点和3个未报告的共享风险位点。将多疾病信号与来自人类、大鼠和小鼠的表达数据集以及表观遗传和表达增强子图谱进行对比时，支持了复杂多效性的存在。这五种免疫疾病之间的共病现象，用生物学多效性而非异质性（一组在基因上与另一种疾病相同的病例，可能是由于诊断错误分类、分子亚型或过度共病）来解释最为合适。特别是，原发性硬化性胆管炎和炎症性肠病之间的强共病现象，可能是一种独特疾病的结果，这种疾病在基因上与经典的炎症性肠病表型不同。
