Molecular Genetics and Behavior: Alcohol and Tobacco Use

描述（由申请人提供）：双胞胎、收养和家庭研究提供的证据表明，基因在酒精和烟草滥用中起着重要作用。此外，流行病学和生物计量遗传学研究表明，酒精和烟草使用之间存在很高的合并症，这可能是由于遗传因素重叠造成的。来自药理学研究和酒精和烟草相关表型小鼠模型研究的证据也支持了相同的神经通路被两种物质激活的假设。最近的证据表明，神经元烟碱受体（nAChRs）是这些药物的关键靶点。已知有几种尼古丁受体参与调节多巴胺对酒精和尼古丁的释放。这些受体（α - 4-6和β - 2-3亚基）可能在调节多巴胺能奖励通路中发挥重要作用，多巴胺能奖励通路与物质使用相关的愉悦感觉密切相关。该项目旨在检查α - 4-6、β - 2-3 nAChR亚基的基因，以了解它们在促进酒精和烟草问题使用的发展中可能发挥的作用。候选人将在兄弟姐妹对样本中检查这些基因，这些样本的DMA和表型数据已经作为国家青少年健康纵向研究（Add Health）的一部分收集。该候选人将利用计算生物信息学方法在这些基因中识别潜在的功能性单核苷酸多态性（snp），以优化选择snp并确定这些基因型。将使用几种统计方法来测试与单个snp或单倍型和酒精或烟草问题使用的关联和/或联系。执行生物信息学和统计遗传学的技能将通过课程、专题讨论会、讲习班、会议和与导师的磋商来发展。

DESCRIPTION (provided by applicant): Twin, adoption, and family studies have provided evidence that genes play an important role in alcohol and tobacco abuse. Moreover, epidemiological and biometrical genetics studies have shown that there is high comorbidity between alcohol and tobacco use, which may be due to overlapping genetic factors. Converging evidence from pharmacological research and the study of mouse models of alcohol- and tobacco-related phenotypes also supports the hypothesis that the same neurological pathways are activated by both substances. Recent evidence has implicated the neuronal nicotinic receptors (nAChRs) as critical targets of these drugs. Several nicotinic receptors are known to be involved in mediating the release of dopamine in response to alcohol and nicotine. These receptors (the alpha4-6 and beta2-3 subunits) may play an important role in regulating the dopaminergic reward pathway, which has been strongly implicated in contributing to the pleasurable feelings associated with substance use. This project seeks to examine the genes for the alpha4-6, beta2-3 nAChR subunits for their possible role in contributing to the development of alcohol and tobacco problem use. The candidate will examine these genes in a sample of sibling pairs for which DMA and phenotypic data have already been collected as a part of the National Longitudinal Study of Adolescent Health (Add Health). The candidate will utilize computational bioinformatics methods to identify potential functional single nucleotide polymorphisms (SNPs) within these genes in order to optimally select the SNPs and determine the genotypes of these in the subjects. Several statistical methods will be used to test for association and/or linkage with individual SNPs or haplotypes and alcohol or tobacco problem use. The skills to perform bioinformatics and statistical genetics will be developed through coursework, symposia, workshops, conferences, and consultations with mentors. Training will take place at the Institute for Behavioral Genetics, a unique environment where the candidate will have regular interactions with experts in behavior genetics and substance use disorders. This project will allow the candidate to achieve her short-term goals of learning computational bioinformatics methods, as well as advanced statistical genetics methods to analyze the data, while accumulating evidence that these genes may contribute to alcohol and tobacco problem use. It will also promote her long-term career goals of establishing an independent research career in behavior genetics of alcohol and tobacco use and provide a foundation for future studies.