Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Heidelberg, Germany.
Addict Biol. 2012 Jan;17(1):171-80. doi: 10.1111/j.1369-1600.2011.00395.x. Epub 2011 Oct 18.
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.
酒精依赖（AD）是全球疾病负担的一个重要促成因素。AD 的病因涉及环境和遗传因素，其遗传率约为 50%。本研究旨在通过全基因组关联研究（GWAS）确定 AD 的易感基因。样本包括 1333 名根据《精神障碍诊断与统计手册》第 4 版确诊为严重 AD 的男性住院患者，以及 2168 名对照。其中包括我们小组之前进行的 GWAS 研究中的 487 名患者和 1358 名对照。所有个体均为德国血统。进行了单标记测试和多基因评分分析，以评估具有小效应的多个标记的综合贡献。位于 ADH1B 和 ADH1C 基因之间的单核苷酸多态性（SNP）rs1789891 达到全基因组显著水平[P = 1.27E-8，优势比（OR）= 1.46]。该区域的其他标记物也与 AD 相关，条件分析表明这些标记物有部分独立的贡献。SNP rs1789891 与 ADH1C 基因的功能 Arg272Gln 变体（P = 1.24E-7，OR = 1.31）完全连锁不平衡，该变体已被报道可改变体外乙醇氧化为乙醛的速度。基于多基因评分的方法产生了显著的结果（P = 9.66E-9）。这是首次对 AD 进行全基因组关联研究，为 ADH 基因簇在 AD 中的作用提供了全基因组显著支持，并提示 AD 的病因存在多基因成分。后一个结果可能表明，还有更多的 AD 易感基因有待发现。
