High alcohol consumption is a risk factor for morbidity and mortality, yet few genetic loci have been robustly associated with alcohol intake. Here, we use U.K. Biobank (n = 125,249) and GERA (n = 47,967) datasets to determine genetic factors associated with extreme population-level alcohol consumption and examine the functional validity of outcomes using model organisms and in silico techniques. We identified six loci attaining genome-wide significant association with alcohol consumption after meta-analysis and meeting our criteria for replication: ADH1B (lead SNP: rs1229984), KLB (rs13130794), BTF3P13 (rs144198753), GCKR (rs1260326), SLC39A8 (rs13107325), and DRD2 (rs11214609). A conserved role in phenotypic responses to alcohol was observed for all genetic targets available for investigation (ADH1B, GCKR, SLC39A8, and KLB) in Caenorhabditis elegans. Evidence of causal links to lung cancer, and shared genetic architecture with gout and hypertension was also found. These findings offer insight into genes, pathways, and relationships for disease risk associated with high alcohol consumption.

中文翻译：

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重度饮酒遗传位点的功能有效性、作用和影响。

大量饮酒是发病和死亡的危险因素，但很少有基因位点与酒精摄入密切相关。在这里，我们使用 UK Biobank (n = 125,249) 和 GERA (n = 47,967) 数据集来确定与极端人口水平饮酒相关的遗传因素，并使用模型生物和计算机技术检查结果的功能有效性。经过荟萃分析并满足我们的复制标准，我们确定了六个基因座与饮酒量在全基因组范围内显着相关：ADH1B（先导 SNP：rs1229984）、KLB（rs13130794）、BTF3P13（rs144198753）、GCKR（rs1260326）、SLC39A8（rs13107325） ）和 DRD2（rs11214609）。在秀丽隐杆线虫中，所有可用于研究的遗传靶标（ADH1B、GCKR、SLC39A8 和 KLB）均在酒精表型反应中观察到保守作用。还发现了与肺癌因果关系以及与痛风和高血压共有的遗传结构的证据。这些发现提供了对与大量饮酒相关的疾病风险的基因、途径和关系的深入了解。