Alternate Phenotypes of Substance Abuse

描述(由申请人提供)： 滥用非法药物的倾向至少部分是由基因决定的。事实上，基因对药物滥用总风险的贡献从大约三分之一到三分之二不等，这取决于药物的类别。然而，尽管物质使用障碍(SOD)，包括与酒精和烟草有关的疾病，有相当大的遗传成分，但赋予这种风险的特定基因一直很难捉摸。毫无疑问，识别肥胖症易感基因的一些困难源于这些表型的潜在病因学复杂性。药物滥用被认为是一种多因素多基因病因，其中许多基因和环境因素对疾病的总体风险都有很小的贡献。增加识别导致肥厚症风险的基因的困难可能是表型的异质性，这些表型传统上被选择用于肥厚症易感性的遗传学研究。对肥胖症的另一种定义可能有助于确定遗传和环境影响。这些可供选择的表型可能是肥皂型和/或数量性状的亚型。使用替代的SUD类别和/或SUD的定量措施可以解决遗传异质性。换句话说，在使用连锁和关联范式寻找潜在的风险基因时，可选择的表型可能提供更强的‘信号’。解开从基因型到表型的复杂途径是寻找药物滥用的单个基因的调查人员面临的最大挑战之一。相同的基因可能会导致不同的表型；相反，表面上相关的行为可能实际上在病因上是无关的，至少在遗传上是这样。表型边界的定义对于成功进行连锁和关联研究以发现易导致药物滥用的基因至关重要。对个别基因的识别将为改进治疗铺平道路，例如，导致高危个体的早期识别、关于不同治疗形式的临床决策的进展以及个性化药物。旨在确定非法药物滥用的更多遗传同质性表型的研究远远落后于酒精和烟草的使用和滥用。非法药物滥用对个人和社会都造成了巨大的健康和经济代价，突出表明迫切需要进行这类研究。

DESCRIPTION (provided by applicant): The propensity to abuse illicit drugs is at least partially determined by genes. In fact, the genetic contribution to the total risk for drug abuse varies from about one-third to two-thirds, depending on the class of drug. Yet, despite the fact that substance use disorders (SUDs), including those involving alcohol and tobacco, have a sizable genetic component, the specific genes that confer this risk have been quite elusive. Undoubtedly, some of the difficulty in identifying the susceptibility genes for SUDs stems from the underlying etiologic complexity of these phenotypes. Drug abuse is presumed to have a multifactorial polygenic etiology in which numerous genes and environmental factors all make small contributions to the overall risk for the illness. Compounding the difficulty in identifying genes that impart risk for SUDs may be the heterogeneous nature of the phenotypes that have traditionally been chosen for genetic studies of the liability toward SUDs. Alternative definitions of SUDs may facilitate the identification of genetic and environmental influences. These alternative phenotypes may be subtypes of SUDs and/or quantitative traits. Using alternative SUD classes and/or quantitative measures of SUDs could resolve genetic heterogeneity. In other words, alternative phenotypes may provide a stronger 'signal' in the search for underlying risk genes using linkage and association paradigms. Untangling the complicated pathway from genotype to phenotype is one of the biggest challenges facing investigators searching for individual genes for substance abuse. The same genes may give rise to varying phenotypes; conversely, behaviors that appear to be related phenotypically may in fact be etiologically unrelated, at least genetically. The definition of phenotypic boundaries is essential to the success of linkage and association studies to find genes predisposing to substance abuse. The identification of individual genes will pave the way for improved treatment by leading to, for example, the early identification of high-risk individuals, advances in clinical decision-making regarding different forms of treatment, and individually tailored drugs. Research aimed at identifying more genetically homogeneous phenotypes for illicit drug abuse lags well behind that for alcohol and tobacco use and abuse. The enormous health and financial costs of illicit drug abuse, both to the individual and to society, underscores the pressing need for such research.