Luo Xingguang, Kranzler Henry R, Zuo Lingjun, Wang Shuang, Schork Nicholas J, Gelernter Joel
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06516, USA.
Am J Hum Genet. 2006 Jun;78(6):973-87. doi: 10.1086/504113. Epub 2006 Apr 11.
The set of alcohol-metabolizing enzymes has considerable genetic and functional complexity. The relationships between some alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes and alcohol dependence (AD) have long been studied in many populations, but not comprehensively. In the present study, we genotyped 16 markers within the ADH gene cluster (including the ADH1A, ADH1B, ADH1C, ADH5, ADH6, and ADH7 genes), 4 markers within the ALDH2 gene, and 38 unlinked ancestry-informative markers in a case-control sample of 801 individuals. Associations between markers and disease were analyzed by a Hardy-Weinberg equilibrium (HWE) test, a conventional case-control comparison, a structured association analysis, and a novel diplotype trend regression (DTR) analysis. Finally, the disease alleles were fine mapped by a Hardy-Weinberg disequilibrium (HWD) measure (J). All markers were found to be in HWE in controls, but some markers showed HWD in cases. Genotypes of many markers were associated with AD. DTR analysis showed that ADH5 genotypes and diplotypes of ADH1A, ADH1B, ADH7, and ALDH2 were associated with AD in European Americans and/or African Americans. The risk-influencing alleles were fine mapped from among the markers studied and were found to coincide with some well-known functional variants. We demonstrated that DTR was more powerful than many other conventional association methods. We also found that several ADH genes and the ALDH2 gene were susceptibility loci for AD, and the associations were best explained by several independent risk genes.
酒精代谢酶组具有相当大的遗传和功能复杂性。一些酒精脱氢酶（ADH）和乙醛脱氢酶（ALDH）基因与酒精依赖（AD）之间的关系长期以来已在许多人群中进行研究，但并不全面。在本研究中，我们对801名个体的病例对照样本中的ADH基因簇内的16个标记（包括ADH1A、ADH1B、ADH1C、ADH5、ADH6和ADH7基因）、ALDH2基因内的4个标记以及38个不连锁的祖先信息标记进行了基因分型。通过哈迪-温伯格平衡（HWE）检验、传统病例对照比较、结构化关联分析和一种新的双倍型趋势回归（DTR）分析来分析标记与疾病之间的关联。最后，通过哈迪-温伯格不平衡（HWD）测量（J）对疾病等位基因进行精细定位。所有标记在对照中均处于HWE，但一些标记在病例中显示出HWD。许多标记的基因型与AD相关。DTR分析表明，ADH5基因型以及ADH1A、ADH1B、ADH7和ALDH2的双倍型与欧裔美国人和/或非裔美国人的AD相关。从所研究的标记中精细定位了影响风险的等位基因，并发现它们与一些知名的功能变异相吻合。我们证明DTR比许多其他传统关联方法更具效力。我们还发现几个ADH基因和ALDH2基因是AD的易感基因座，并且这些关联最好由几个独立的风险基因来解释。
