Genome-wide analysis identifies gallstone-susceptibility loci including genes regulating gastrointestinal motility
Genome-wide analysis identifies gallstone-susceptibility loci including genes regulating gastrointestinal motility
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DOI：
10.1002/hep.32199
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发表时间：
2021-12-10
期刊：
影响因子：
13.5
通讯作者：
Harrison, Ewen M.
中科院分区：
文献类型：
--
作者：
Fairfield, Cameron J.;Drake, Thomas M.;Harrison, Ewen M.
背景和目的全基因组关联研究（GWAS）已经确定了几个胆石病的风险位点。与大多数多基因性状一样，可能有许多遗传决定因素尚未发现。这项研究的目的是确定代表胆结石研究和治疗新靶点的遗传变异。方法和结果我们在英国生物库中对28，627例胆结石病例和348，373例对照进行了GWAS，在苏格兰队列中复制了结果（1089例病例，5228例对照），并对FinnGen队列进行了GWA荟萃分析（43，639例病例，506，798例对照）。我们使用基于基因的基因集分析和在基因型-组织表达项目数据中鉴定的基因的组织表达来评估途径富集。我们构建了一个多基因风险评分（PRS），并评估与评分相关的表型性状。75个风险位点被确定（p < 5 × 10（-8）），其中46个是新的。途径富集揭示了与脂质稳态、葡萄糖醛酸化、磷脂代谢和胃肠动力的相关性。Anoctamin 1（ANO 1）和跨膜蛋白147（TMEM 147），都在新的，复制的基因座，在胆囊和胃肠道中表达。两者都调节胃肠蠕动。胆结石风险等位基因rs7599-A导致肝TMEM 147表达的抑制，表明该蛋白质保护胆结石形成。与最低十分位数相比，PRS的最高十分位数显示胆结石的几率增加了6倍。PRS与体重指数、血清肝酶和C-反应蛋白浓度升高以及脂蛋白胆固醇浓度降低密切相关。结论GWAS显示了胆囊结石风险的多基因性，并确定了46个新的易感基因位点。我们牵连基因影响胃肠动力的发病机制中的胆结石。
Background and Aims Genome-wide association studies (GWAS) have identified several risk loci for gallstone disease. As with most polygenic traits, it is likely that many genetic determinants are undiscovered. The aim of this study was to identify genetic variants that represent new targets for gallstone research and treatment. Approach and Results We performed a GWAS of 28,627 gallstone cases and 348,373 controls in the UK Biobank, replicated findings in a Scottish cohort (1089 cases, 5228 controls), and conducted a GWA meta-analysis (43,639 cases, 506,798 controls) with the FinnGen cohort. We assessed pathway enrichment using gene-based then gene-set analysis and tissue expression of identified genes in Genotype-Tissue Expression project data. We constructed a polygenic risk score (PRS) and evaluated phenotypic traits associated with the score. Seventy-five risk loci were identified (p < 5 x 10(-8)), of which 46 were new. Pathway enrichment revealed associations with lipid homeostasis, glucuronidation, phospholipid metabolism, and gastrointestinal motility. Anoctamin 1 (ANO1) and transmembrane Protein 147 (TMEM147), both in novel, replicated loci, are expressed in the gallbladder and gastrointestinal tract. Both regulate gastrointestinal motility. The gallstone risk allele rs7599-A leads to suppression of hepatic TMEM147 expression, suggesting that the protein protects against gallstone formation. The highest decile of the PRS demonstrated a 6-fold increased odds of gallstones compared with the lowest decile. The PRS was strongly associated with increased body mass index, serum liver enzymes, and C-reactive protein concentrations, and decreased lipoprotein cholesterol concentrations. Conclusions This GWAS demonstrates the polygenic nature of gallstone risk and identifies 46 novel susceptibility loci. We implicate genes influencing gastrointestinal motility in the pathogenesis of gallstones.