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，很少研究人类遗传多态性与SUD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基因多态性与SUD风险之间的关联。我们的具体目标是：目标1。利用基于家族的方法，分别评估多巴胺受体和MAOA基因的已知多态性与物质依赖倾向的关系，这些多态性与物质依赖倾向的关系是通过通过DSM-IV诊断为物质依赖的青少年男性确定的350个家庭，以及基于群体的方法，在成年病例对照的男性和女性样本和青少年男性病例对照样本中确定的；目标2。a)在以家庭为基础的样本中，利用所有检测到的多态性确定受试者每个位点的单倍型；b)在测量单倍型分析中使用单倍型数据确定影响SUD风险的多态性；目标3。a)确定DNA多态性对人格特征的影响，无论是在单个位点水平上，还是作为单倍型共同考虑；b)评价人格特征对物质依赖倾向与DNA多态性之间关系的影响；和Aim 4。评估环境因素（例如，不良的个人生活经历、与不良同伴的关系、高环境犯罪率）对物质依赖责任变异的影响及其与遗传多态性的关系。提出的研究将检查DNA多态性，个性和环境因素在变异对SUD的责任中的作用。尽管单个基因的影响可能很小，但由于人群中高风险相关等位基因的频率很高，其归因风险可能很大。它们的综合影响可能是巨大的。此外，基于遗传机制对人群中SUD风险变异的影响的认识，可以制定药物滥用预防措施，其效果可能大于此类机制的“自然”贡献。结果将允许更准确地估计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.