Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett's oesophagus and provides insights into clinical heterogeneity in reflux diagnosis.
Multitrait genetic association analysis identifies 50 new risk loci for gastro-oesophageal reflux, seven new loci for Barrett's oesophagus and provides insights into clinical heterogeneity in reflux diagnosis.
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DOI：
10.1136/gutjnl-2020-323906
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发表时间：
2022-06
期刊：
影响因子：
24.5
通讯作者：
MacGregor, Stuart
中科院分区：
文献类型：
--
作者：
Ong, Jue-Sheng;An, Jiyuan;Han, Xikun;Law, Matthew H.;Nandakumar, Priyanka;Schumacher, Johannes;Gockel, Ines;Bohmer, Anne;Jankowski, Janusz;Palles, Claire;Olsen, Catherine M.;Neale, Rachel E.;Fitzgerald, Rebecca;Thrift, Aaron P.;Vaughan, Thomas L.;Buas, Matthew F.;Hinds, David A.;Gharahkhani, Puya;Kendall, Bradley J.;MacGregor, Stuart
胃食道反流病(GERD)具有异质性的病因学，主要归因于其基于症状的定义。Gerd全基因组关联研究(GWASs)显示，与肥胖和抑郁症等既定风险因素有很强的遗传重叠。我们假设GERD和这些危险因素之间的共同遗传结构可以被用来(1)识别新的GERD和Barrett‘s食道(BE)危险基因座，以及(2)探索潜在的导致GERD和食道并发症的不同途径。我们应用了多性状 模型，结合了GERD(78例 707例；288例GWF734对照)和遗传相关特征，包括教育程度、抑郁和体重指数。我们还使用多性状分析来确定BE风险基因座。在23andMe中复制了最高命中率(462例 753例GERD，24例 099 BE，1例 484 025对照)。此外，我们还将GERD基因座分成肥胖驱动亚组和抑郁驱动亚组。研究人员对这些亚组进行了调查，以确定它们与组织特异性基因表达和严重食道疾病(BE和/或食管腺癌)风险的关系。我们确定了88个与GERD相关的基因座，其中59个在23andMe中重复。我们的BE分析确定了7个新的基因座。此外，我们还发现，只有肥胖驱动的GERD基因(而不是抑郁驱动的基因)与富含在食道组织中的基因相关，并成功地预测了BE/EA。我们的多性状模型确定了许多新的GERD和BE的危险基因。我们提出了强有力的证据，证明了GERD疾病异质性的遗传基础，并表明与抑郁症状相关的GERD基因座与肥胖驱动的GERD基因座相比，并不是BE/EA的有力预测因子。
Gastro-oesophageal reflux disease (GERD) has heterogeneous aetiology primarily attributable to its symptom-based definitions. GERD genome-wide association studies (GWASs) have shown strong genetic overlaps with established risk factors such as obesity and depression. We hypothesised that the shared genetic architecture between GERD and these risk factors can be leveraged to (1) identify new GERD and Barrett’s oesophagus (BE) risk loci and (2) explore potentially heterogeneous pathways leading to GERD and oesophageal complications. We applied multitrait GWAS models combining GERD (78 707 cases; 288 734 controls) and genetically correlated traits including education attainment, depression and body mass index. We also used multitrait analysis to identify BE risk loci. Top hits were replicated in 23andMe (462 753 GERD cases, 24 099 BE cases, 1 484 025 controls). We additionally dissected the GERD loci into obesity-driven and depression-driven subgroups. These subgroups were investigated to determine how they relate to tissue-specific gene expression and to risk of serious oesophageal disease (BE and/or oesophageal adenocarcinoma, EA). We identified 88 loci associated with GERD, with 59 replicating in 23andMe after multiple testing corrections. Our BE analysis identified seven novel loci. Additionally we showed that only the obesity-driven GERD loci (but not the depression-driven loci) were associated with genes enriched in oesophageal tissues and successfully predicted BE/EA. Our multitrait model identified many novel risk loci for GERD and BE. We present strong evidence for a genetic underpinning of disease heterogeneity in GERD and show that GERD loci associated with depressive symptoms are not strong predictors of BE/EA relative to obesity-driven GERD loci.
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