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，遗传因素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，尽管包括酒精和烟草在内的物质使用障碍（SUD）具有相当大的遗传成分，但赋予这种风险的特定基因一直非常难以捉摸。毫无疑问，确定SUD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学，其中许多基因和环境因素都对疾病的总体风险贡献很小。确定SUD风险基因的困难可能是传统上选择用于SUD易感性遗传研究的表型的异质性。SUD的替代定义可能有助于识别遗传和环境影响。这些替代表型可以是SUD和/或数量性状的亚型。使用替代SUD类和/或SUD的定量测量可以解决遗传异质性。换句话说，替代表型可以提供一个更强的“信号”，在寻找潜在的风险基因使用连锁和关联的范例。解开从基因型到表型的复杂途径是研究人员寻找药物滥用个体基因所面临的最大挑战之一。相同的基因可能会产生不同的表型;相反，表现上似乎相关的行为实际上可能在病因学上无关，至少在遗传学上是如此。表型边界的定义是必不可少的成功的连锁和关联研究，以找到易患药物滥用的基因。识别个别基因将为改进治疗铺平道路，例如，导致早期识别高风险个体，在不同治疗形式的临床决策方面取得进展，以及个体定制药物。旨在确定遗传上更为同质的非法药物滥用表型的研究远远落后于酒精和烟草使用和滥用的研究。非法药物滥用给个人和社会造成的巨大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.