Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.
Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.
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DOI：
10.1038/ng.3528
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发表时间：
2016-05
期刊：
影响因子：
30.8
通讯作者：
Franke A
中科院分区：
文献类型：
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作者：
Ellinghaus D;Jostins L;Spain SL;Cortes A;Bethune J;Han B;Park YR;Raychaudhuri S;Pouget JG;Hübenthal M;Folseraas T;Wang Y;Esko T;Metspalu A;Westra HJ;Franke L;Pers TH;Weersma RK;Collij V;D'Amato M;Halfvarson J;Jensen AB;Lieb W;Degenhardt F;Forstner AJ;Hofmann A;International IBD Genetics Consortium (IIBDGC);International Genetics of Ankylosing Spondylitis Consortium (IGAS);International PSC Study Group (IPSCSG);Genetic Analysis of Psoriasis Consortium (GAPC);Psoriasis Association Genetics Extension (PAGE);Schreiber S;Mrowietz U;Juran BD;Lazaridis KN;Brunak S;Dale AM;Trembath RC;Weidinger S;Weichenthal M;Ellinghaus E;Elder JT;Barker JN;Andreassen OA;McGovern DP;Karlsen TH;Barrett JC;Parkes M;Brown MA;Franke A
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景观，以研究多效性和这些临床相关疾病之间的关系。使用来自超过86，000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基因座和3个未报告的共享风险基因座。当将多疾病信号与来自人、大鼠和小鼠的表达数据集以及表观遗传和表达的增强子谱进行对比时，支持复杂的多效性。五种免疫疾病的共病最好用生物多效性来解释，而不是异质性（与另一种疾病在遗传上相同的病例亚组，可能是由于诊断错误分类，分子亚型或过度的共病）。特别是，原发性硬化性胆管炎和炎症性肠病之间的强烈共病可能是一种独特疾病的结果，这种疾病在遗传上与经典的炎症性肠病表型不同。
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 multi-disease signals including 27 novel genome-wide significant susceptibility loci and 3 unreported shared risk loci. Complex pleiotropy was supported when contrasting multi-disease signals with expression data sets from human, rat and mouse, and 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 that is genetically identical to another disease, possibly due 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.