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解开这些因素。然而，很少有人研究人类基因多态性与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参与了物质滥用的风险。此外，我们的试验数据支持多巴胺D5受体和MAOA基因多态性与SUD风险之间的关联。 我们有以下具体目标：目标1。评价已知的多巴胺受体和MAOA基因的多态性，分别和作为单倍型，其与物质依赖的易感性的关联，使用基于家庭的方法，在350个家庭中，通过一名患有药物依赖的DSM-IV诊断的青少年男性确定，并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人群的方法;目的2。a）在基于家族的样本中，使用所有检测到的多态性确定每个基因座的受试者的单倍型; B）使用测量的单倍型分析中的单倍型数据确定影响SUD风险的多态性;目的3. a）确定DNA多态性对人格特征的影响，无论是在单个基因座的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和DNA多态性之间的关联的影响;以及目的4。 评估环境因素的影响（例如，不良的个人生活经历，与犯罪同龄人的联系，高环境犯罪）对物质依赖倾向的变化及其与遗传多态性的关系。这项研究将探讨DNA多态性、个性和环境因素在SUD易感性变化中的作用。 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，因此其归因风险可能很大。它们的综合影响可能是巨大的。 此外，根据对导致人口中SUD风险变异的遗传机制的了解，可以制定预防药物滥用措施，其效果可能大于这种机制的“自然”贡献。 这些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.