Department of Human and Molecular Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, USA.
Alcohol Clin Exp Res. 2011 Feb;35(2):376-85. doi: 10.1111/j.1530-0277.2010.01353.x. Epub 2010 Nov 17.
Over 50 years of evidence from research has established that the central dopaminergic reward pathway is likely involved in alcohol dependence (AD). Additional evidence supports a role for dopamine (DA) in other disinhibitory psychopathology, which is often comorbid with AD. Family and twin studies demonstrate that a common genetic component accounts for most of the genetic variance in these traits. Thus, DA-related genes represent putative candidates for the genetic risk that underlies not only AD but also behavioral disinhibition. Many linkage and association studies have examined these relationships with inconsistent results, possibly because of low power, poor marker coverage, and/or an inappropriate correction for multiple testing.
We conducted an association study on the products encoded by 10 DA-related genes (DRD1-D5, SLC18A2, SLC6A3, DDC, TH, COMT) using a large, ethnically homogeneous sample with severe AD (n = 545) and screened controls (n = 509). We collected genotypes from linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) and employed a gene-based method of correction. We tested for association with AD diagnosis in cases and controls and with a variety of alcohol-related traits (including age-at-onset, initial sensitivity, tolerance, maximum daily drinks, and a withdrawal factor score), disinhibitory symptoms, and a disinhibitory factor score in cases only. A total of 135 SNPs were genotyped using the Illumina GoldenGate and Taqman Assays-on-Demand protocols.
Of the 101 SNPs entered into standard analysis, 6 independent SNPs from 5 DA genes were associated with AD or a quantitative alcohol-related trait. Two SNPs across 2 genes were associated with a disinhibitory symptom count, while 1 SNP in DRD5 was positive for association with the general disinhibitory factor score.
Our study provides evidence of modest associations between a small number of DA-related genes and AD as well as a range of alcohol-related traits and measures of behavioral disinhibition. While we did conduct gene-based correction for multiple testing, we did not correct for multiple traits because the traits are correlated. However, false-positive findings remain possible, so our results must be interpreted with caution.
超过 50 年的研究证据表明，中枢多巴胺奖赏途径可能与酒精依赖（AD）有关。其他证据支持多巴胺（DA）在其他抑制性精神病理学中的作用，而这些精神病理学通常与 AD 共病。家族和双胞胎研究表明，一个常见的遗传成分解释了这些特征的大部分遗传变异。因此，与 DA 相关的基因代表了潜在的候选基因，不仅与 AD 有关，而且与行为抑制解除有关。许多连锁和关联研究都检查了这些关系，但结果不一致，这可能是由于功效低、标记覆盖率差和/或对多重检验的不当校正。
我们使用一个大的、种族同质性的严重 AD 样本（n=545）和筛选对照（n=509），对 10 个与 DA 相关的基因（DRD1-D5、SLC18A2、SLC6A3、DDC、TH、COMT）的编码产物进行了关联研究。我们从连锁不平衡（LD）标记单核苷酸多态性（SNP）中收集基因型，并采用基于基因的校正方法。我们在病例和对照中以及在病例中与各种酒精相关特征（包括发病年龄、初始敏感性、耐受性、最大每日饮酒量和戒断因子评分）、抑制解除症状和抑制解除因子评分方面，对 AD 诊断进行了关联测试。使用 Illumina GoldenGate 和 Taqman Assays-on-Demand 方案对总共 135 个 SNP 进行了基因分型。
在进入标准分析的 101 个 SNP 中，来自 5 个 DA 基因的 6 个独立 SNP 与 AD 或定量酒精相关特征相关。2 个基因中的 2 个 SNP 与抑制解除症状计数相关，而 DRD5 中的 1 个 SNP 与一般抑制解除因子评分呈阳性相关。
我们的研究提供了一些证据，表明一小部分与 DA 相关的基因与 AD 以及一系列与酒精相关的特征和行为抑制解除的测量值之间存在适度的关联。虽然我们确实对多重测试进行了基于基因的校正，但我们没有对多个特征进行校正，因为这些特征是相关的。然而，仍然可能存在假阳性发现，因此我们的结果必须谨慎解释。
