Which alcohol use disorder criteria contribute to the association of ADH1B with alcohol dependence?
Which alcohol use disorder criteria contribute to the association of ADH1B with alcohol dependence?
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DOI：
10.1111/adb.12244
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发表时间：
2016-07-01
影响因子：
3.4
通讯作者：
Kranzler, Henry R.
中科院分区：
文献类型：
--
作者：
Hart, Amy B.;Lynch, Kevin G.;Kranzler, Henry R.
虽然酒精依赖（AD）约有50%是遗传的，但对特定的遗传位点如何影响AD风险知之甚少。在一项全基因组关联研究（GWAS）中，我们确定了非裔美国人（AAs; rs 2066702）和欧裔美国人（EAs; rs 1229984）中乙醇脱氢酶1B基因（ADH 1B）中两种人群特异性功能变体与AD之间的高度显著关联。在目前的研究中，我们确定了哪些特定的诊断标准有助于观察到的ADH 1B SNP与AD的关联。我们的分析包括DSM-4和DSM-5诊断系统。我们还研究了ADH 1B变体与24小时内最大饮酒量（MaxDrinks）的关系，这是一种推测的AD中间表型。我们发现，尽管所有标准都对这些关联做出了强有力的个人贡献，但最大的贡献来自那些反映神经适应的标准：耐受性（rs 2066702）和退缩（rs 1229984）。总体而言，与DSM-5标准相关的证据略强于DSM-IV标准。对于rs 2066702，DSM-IV和DSM-5标准的结果相似。然而，与rs 1229984相关的最重要的DSM-5标准是与酒精相关的社会/人际问题。这两种ADH 1B变体都与MaxDrinks（一种先天耐受性指标）相关，MaxDrinks介导了ADH 1B与酒精结果之间的关联。我们在一个独立的AA样本中复制了rs 2066702和耐受性的发现。综上所述，这些结果表明，ADH 1B的变化影响了对大量饮酒的适应，突出了AUD遗传风险的人群特异性差异。他们还认为DSM-5 AUD中反映的修订可能会增强基因发现诊断的实用性。
Although alcohol dependence (AD) is approximately 50% heritable, little is known about how specific genetic loci affect AD risk. In a genome-wide association study (GWAS), we identified highly significant associations between two population-specific functional variants in the alcohol dehydrogenase 1B gene (ADH1B) and AD in African-Americans (AAs; rs2066702) and European-Americans (EAs; rs1229984). In the current study, we determined which specific diagnostic criteria contributed to the observed associations of ADH1B SNPs with AD. Our analysis included both the DSM-IV and DSM-5 diagnostic systems. We also investigated the relationship of ADH1B variants to the maximum number of drinks consumed in a 24-hour period (MaxDrinks), a presumed intermediate phenotype of AD. We found that, although all criteria made strong individual contributions to the associations, the largest contributions came from those reflecting neuroadaptation: tolerance (rs2066702) and withdrawal (rs1229984). Overall, evidence for association with DSM-5 criteria was slightly stronger than for DSM-IV criteria. For rs2066702, results were similar for DSM-IV and DSM-5 criteria. However, the most significant DSM-5 criterion associated with rs1229984 was alcohol-related social/interpersonal problems. Both ADH1B variants were associated with MaxDrinks, a measure of innate tolerance, and MaxDrinks mediated the associations between ADH1B and alcohol outcomes. We replicated the findings for rs2066702 and tolerance in an independent sample of AAs. Taken together, these results suggest that variation in ADH1B affects the adaptation to heavy drinking, highlighting population-specific differences in genetic risk for AUD. They also suggest that the revisions reflected in DSM-5 AUD may enhance the utility of that diagnosis for gene finding.