Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.
Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.
复制标题
DOI：
10.1136/gutjnl-2020-323868
复制
发表时间：
2021-04-22
期刊：
影响因子：
24.5
通讯作者：
Franke A
中科院分区：
文献类型：
--
作者：
Zheng T;Ellinghaus D;Juzenas S;Cossais F;Burmeister G;Mayr G;Jørgensen IF;Teder-Laving M;Skogholt AH;Chen S;Strege PR;Ito G;Banasik K;Becker T;Bokelmann F;Brunak S;Buch S;Clausnitzer H;Datz C;DBDS Consortium;Degenhardt F;Doniec M;Erikstrup C;Esko T;Forster M;Frey N;Fritsche LG;Gabrielsen ME;Gräßle T;Gsur A;Gross J;Hampe J;Hendricks A;Hinz S;Hveem K;Jongen J;Junker R;Karlsen TH;Hemmrich-Stanisak G;Kruis W;Kupcinskas J;Laubert T;Rosenstiel PC;Röcken C;Laudes M;Leendertz FH;Lieb W;Limperger V;Margetis N;Mätz-Rensing K;Németh CG;Ness-Jensen E;Nowak-Göttl U;Pandit A;Pedersen OB;Peleikis HG;Peuker K;Rodriguez CL;Rühlemann MC;Schniewind B;Schulzky M;Skieceviciene J;Tepel J;Thomas L;Uellendahl-Werth F;Ullum H;Vogel I;Volzke H;von Fersen L;von Schönfels W;Vanderwerff B;Wilking J;Wittig M;Zeissig S;Zobel M;Zawistowski M;Vacic V;Sazonova O;Noblin ES;23andMe Research Team;Farrugia G;Beyder A;Wedel T;Kahlke V;Schafmayer C;D'Amato M;Franke A
痔疮病（HEM）影响了一个大的和默默受苦的人口比例，但其病因，包括可疑的遗传易感性，是知之甚少。我们报告了第一个全基因组关联研究（GWAS）荟萃分析，以确定迄今为止HEM的遗传危险因素。我们对218920例HEM患者和725213例欧洲血统对照者进行了GWAS荟萃分析。使用GWAS汇总统计量，我们进行了HEM和其他性状之间的多重遗传相关性分析，并计算了HEM多基因风险评分（PRS），并在独立数据集中评估了它们的翻译潜力。使用GWAS结果的功能注释，我们鉴定了HEM候选基因，使用RNA-seq分析评估了HEM组织中的差异表达和共表达。通过免疫组织化学研究在选定位点表达的蛋白质的定位。我们证明了适度的遗传性和遗传相关性HEM与其他几种疾病从胃肠道，神经情感和心血管领域。HEM PRS在来自独立数据集的180 435名个体中进行了验证，可以识别风险人群，并与发病年龄和复发手术相关。我们确定了102个独立的HEM风险基因座，这些基因的表达在血管和GI组织中富集，并且在与平滑肌、上皮和内皮发育和形态发生相关的途径中富集。网络转录组学分析突出了HEM基因共表达模块，这些模块与肌肉骨骼和表皮系统的发育和完整性以及细胞外基质的组织相关。HEM有一种遗传成分，易导致平滑肌、上皮和结缔组织功能障碍。
Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date. We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry. We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix. HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.
登录
查看更多内容
影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
影响因子：
14.9
作者：
Buniello, Annalisa;MacArthur, Jacqueline A. L.;Parkinson, Helen
通讯作者：
Parkinson, Helen
DOI：
10.1161/atvbaha.119.313658
发表时间：
2020-03-01
影响因子：
8.7
作者：
Groot, Hilde E.;Sierra, Laura E. Villegas;van der Harst, Pim
通讯作者：
van der Harst, Pim
影响因子：
9.8
作者：
DeBoever, Christopher;Tanigawa, Yosuke;Rivas, Manuel A.
通讯作者：
Rivas, Manuel A.