SUBSTANCE ABUSE AND THE DOPAMINE SYSTEM GENES

物质使用障碍(SUD)风险的变化是遗传和环境因素相互作用的结果。分子遗传学研究可能有助于理清这些因素。然而，很少有人研究人类基因多态与SUD易感性的关系。在这些基因座中，编码多巴胺受体和单胺氧化酶A(MAOA)的基因引起了特别的关注，因为它们被证明或假设与药物滥用的风险有关。此外，我们的试点数据支持多巴胺D5受体和MAOA基因的多态与SUD风险之间的关联。我们有以下具体目标：目的1.在350个通过DSM-IV诊断为物质依赖的青少年男性确定的家庭中，使用基于家庭的方法，以及在成年病例对照男性和女性样本以及青少年男性病例对照样本中，使用基于群体的方法，分别评估已知的多巴胺受体和MAOA基因的多态和单倍型与物质依赖易感性的关联；目的2.在基于家庭的样本中，使用所有检测到的多态来确定受试者每个基因的单倍型；b)使用测量的单倍型分析中的单倍型数据来确定影响SUD风险的多态；目的3)在个体基因座水平上确定DNA多态对人格特征的影响；b)评估人格特征对物质依赖易感性与DNA多态之间关联的影响；以及4.评估环境因素(如不良的个人生活经历、与犯罪同龄人的关系、高环境犯罪)对物质依赖易感性的影响及其与基因多态的关系。这项拟议的研究将考察DNA多态、个性和环境因素在SUD易感性变异中的作用。尽管单基因的影响可能很小，但它们的归因风险可能很大，因为人群中高风险相关等位基因的频率很高。它们的综合影响可能是巨大的。此外，基于对导致人群中SUD风险变化的遗传机制的了解而制定的药物滥用预防措施的影响可能比这种机制的“自然”贡献更大。这一结果将有助于更准确地估计SUD的风险，并提出预防方法。

Variation in the risk for substance use disorder (SUD) results from the interaction of genetic and environmental factors. Molecular genetic studies may help disentangle these factors. Few human genetic polymorphisms, however, have been studied in relation to the liability to SUD. Among these loci, the genes encoding dopamine receptors and monoamine oxidase A (MAOA) attract special attention because of their demonstrated or hypothesized involvement in the risk for substance abuse. Furthermore, our pilot data support an association between polymorphisms at the dopamine D5 receptor and MAOA genes and the risk for SUD. We have the following specific aims: Aim 1. Evaluate known polymorphisms at the dopamine receptor and MAOA genes, separately and as haplotypes, for their association with the liability to substance dependence using family-based methods in 350 families ascertained via an adolescent male with a DSM-IV diagnosis of substance dependence, and population-based methods in both adult case-control male and female samples and adolescent male case-control sample; Aim 2. a) In the family-based sample, determine subjects' haplotypes for each locus using all detected polymorphisms; b) Determine polymorphisms affecting SUD risk using the haplotype data in a measured haplotype analysis; Aim 3. a) Determine the influence of DNA polymorphisms, both at the level of individual loci and considered jointly as haplotypes, on personality characteristics; b) Evaluate the influence of personality characteristics on the association between the liability to substance dependence and the DNA polymorphisms; and Aim 4. Evaluate the effects of environmental factors (e.g., adverse individual life experiences, affiliation with delinquent peers, high environmental crime) on the variation in liability to substance dependence and its relationship with genetic polymorphisms. The proposed research will examine the role of DNA polymorphisms, personality and environmental factors in variation in the liability to SUD. Even though the effects of single genes may be small, their attributable risk may be large because of a high frequency of high-risk-associated alleles in the population. Their combined effect may be substantial. Moreover, the effect of measures of drug abuse prevention that could be developed based on the knowledge of genetic mechanisms contributing into the SUD risk variation in the population may be greater than the "natural" contribution of such mechanisms. The results will allow for more accurate estimation of the risk for SUD and suggest approaches for prevention.