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Genome-wide significant association between alcohol dependence and a variant in the ADH gene cluster

机译：酒精依赖与ADH基因簇变异之间的全基因组显着关联

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Alcohol dependence (AD) is an important contributory factor to the global burden of disease. The etiology of AD involves both environmental and genetic factors, and the disorder has a heritability of around 50%. The aim of the present study was to identify susceptibility genes for AD by performing a genome-wide association study (GWAS). The sample comprised 1333 male in-patients with severe AD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, and 2168 controls. These included 487 patients and 1358 controls from a previous GWAS study by our group. All individuals were of German descent. Single-marker tests and a polygenic score-based analysis to assess the combined contribution of multiple markers with small effects were performed. The single nucleotide polymorphism (SNP) rs1789891, which is located between the ADH1B and ADH1C genes, achieved genome-wide significance [P = 1.27E-8, odds ratio (OR) = 1.46]. Other markers from this region were also associated with AD, and conditional analyses indicated that these made a partially independent contribution. The SNP rs1789891 is in complete linkage disequilibrium with the functional Arg272Gln variant (P = 1.24E-7, OR = 1.31) of the ADH1C gene, which has been reported to modify the rate of ethanol oxidation to acetaldehyde in vitro. A polygenic score-based approach produced a significant result (P = 9.66E-9). This is the first GWAS of AD to provide genome-wide significant support for the role of the ADH gene cluster and to suggest a polygenic component to the etiology of AD. The latter result may indicate that many more AD susceptibility genes still await identification.
机译：酒精依赖（AD）是造成全球疾病负担的重要因素。 AD的病因涉及环境和遗传因素，该疾病的遗传力约为50％。本研究的目的是通过进行全基因组关联研究（GWAS）来确定AD的易感基因。根据《精神疾病诊断和统计手册》（第4版）和2168对照，该样本包括1333名重度AD男性住院患者。这包括来自我们小组先前的GWAS研究的487位患者和1358位对照。所有个人都是德国血统。进行了单标记测试和基于多基因得分的分析，以评估多个标记的综合作用，且影响很小。位于ADH1B和ADH1C基因之间的单核苷酸多态性（SNP）rs1789891实现了全基因组意义[P = 1.27E-8，优势比（OR）= 1.46]。来自该区域的其他标志物也与AD相关，条件分析表明这些标志物部分地是独立的。 SNP rs1789891与ADH1C基因的功能性Arg272Gln变体（P = 1.24E-7，OR = 1.31）处于完全连锁不平衡状态，据报道该变体可在体外改变乙醇氧化为乙醛的速率。基于多基因评分的方法产生了显着结果（P = 9.66E-9）。这是AD的第一个GWAS，它为ADH基因簇的作用提供全基因组范围内的重要支持，并为AD的病因提供了多基因成分。后一结果可能表明还有更多的AD易感基因仍在等待鉴定。

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