Serotonin, dopamine and GABA systems in the development of alcohol use disorder

酒精使用障碍发展中的血清素、多巴胺和 GABA 系统

• 批准号: 7781011
• 负责人: Sandra Maria Villafuerte
• 金额: $ 3.86万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-25 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7781011
• 关键词: 21 year old; 5 year old; Affect; Age; Age of Onset; Alcohol abuse; Alcoholism; Alcohols; Anxiety; Behavioral; Biological; Brain; Budgets; Candidate Disease Gene; Child; Child Abuse; Child Abuse and Neglect; Clinical; Cognitive; Communities; Complex; DSM-IV; Data; Data Collection; Development; Diagnosis; Dopamine; Emotional; Environment; Environmental Risk Factor; Equilibrium; Esthesia; Etiology; Family; Family member; Fathers; Female; Frequencies; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Haplotypes; Health; Heterogeneity; Hostility; Impulsivity; Individual; Institutes; Laboratories; Left; Life; Life Cycle Stages; Literature; Longitudinal Studies; Measures; Merlin-2; Methods; Michigan; Modeling; Mothers; National Institute on Alcohol Abuse and Alcoholism; Nature; Neurotransmitters; Nuclear Family; Parents; Pathway interactions; Personality; Phenotype; Preventive Intervention; Recruitment Activity; Research; Rest; Risk; Risk Assessment; Risk Factors; Role; SNP genotyping; Sampling; Serotonin; Severities; Siblings; Signal Transduction; Social Environment; Social Functioning; Son; Stratification; Substance abuse problem; Susceptibility Gene; Symptoms; System; Technology; Temperament; Testing; Time; Universities; Variant; addiction; alcohol response; alcohol use disorder; base; boys; depression; depressive symptoms; design; disorder risk; endophenotype; experience; follow-up; gamma-Aminobutyric Acid; gene environment interaction; gene interaction; genetic variant; improved; interest; male; model design; offspring; proband; problem drinker; prospective; public health relevance; relating to nervous system; trait

DESCRIPTION (provided by applicant): The causes of Alcohol Use Disorder (AUD) are complex, with genetic and environmental contributions. Several behavioral phenotypes are closely associated with and precede AUD in the life course. We propose to investigate genetic susceptibility, gene-gene, and gene-environment interactions for the development of AUD. We will focus on three major neurotransmitter systems implicated in the neural excitation-inhibition balance, serotonergic, dopaminergic and GABAergic pathways. Homeostatic plasticity driven by this balance is necessary for adequate information transfer in the brain. We will perform association tests between these genes and behavioral phenotypes that measure under-control and negative affectivity, two of the most clearly identified behavioral endophenotypes that increase risk for transitioning from experimentation into problem use, as well as with phenotypes that measure progression into AUD severity, the lifetime alcohol problems score, and diagnosis, with age of onset as a covariate, and a longitudinal model designed by Dr. Jester that measures the number of alcohol symptoms (DSM-IV) over time in the parents. For gene-environment interactions we will consider a retrospective measure of childhood maltreatment. The research will be conducted using data from the ongoing Michigan Longitudinal Study (MLS), a prospective community ascertained study of 466 families at varying risk for alcoholism that has been ongoing for over 20 years (954 parents and 1003 offspring), with assessments at 3-year intervals and yearly between ages 11 and 17. We have obtained funding from the University of Michigan to genotype the 528 most informative individuals for 1536 SNPs (1430 SNPs from 132 addiction-relevant candidate genes and 106 genomic controls SNPs) from an "addiction panel" designed by David Goldman (NIAAA), using the Illumina GoldenGate technology which has been used nationwide to analyze addiction-related traits. Because the panel also includes SNPs to measure ethnic stratification, it will also alleviate concerns about heterogeneity. Specific aims for this proposal are: 1) Identify genetic polymorphisms from the serotonin, dopamine and GABA pathways involved in behavioral traits (behavioral under-control and negative affectivity traits) that increase risk for alcohol used disorders (AUDs). 2) From these same set of genes identify genetic variants that influence progression into AUD severity. 3) Determine if childhood abuse interacts with genetic variants associated with progression into AUD severity. Genetic variation in these genes may influence the neural excitation-inhibition balance and in turn may impact behavioral traits that increase risk to develop AUDs and interact with environmental factors such as childhood abuse. The PI will gain experience in the statistical approaches of gene-environment and gene-gene interactions, longitudinal models and further advance her understanding of behavioral risk factors to develop AUDs. The PI will be able to add the genetic expertise to the MLS research group. PUBLIC HEALTH RELEVANCE: This study intends to understand the genetic and environmental risk and protective factors involved in the etiology of alcohol use disorders. The identification of these risk or protective factors will help to better screen vulnerable subjects, improve risk assessment, delineate preventive interventions and facilitate appropriate treatment.

描述（由申请人提供）：酒精使用障碍（AUD）的原因是复杂的，遗传和环境的贡献。在生命过程中，几种行为表型与AUD密切相关并先于AUD。我们建议调查遗传易感性，基因-基因，基因-环境相互作用的发展AUD。我们将集中在三个主要的神经递质系统涉及的神经兴奋抑制平衡，多巴胺能，多巴胺能和γ-氨基丁酸能途径。由这种平衡驱动的稳态可塑性对于大脑中充分的信息传递是必要的。我们将在这些基因和行为表型之间进行关联测试，这些表型测量控制不足和消极情感，这两种最明确的行为内在表型增加了从实验过渡到问题使用的风险，以及测量进展到AUD严重程度的表型，终身酒精问题评分和诊断，发病年龄作为协变量，Jester博士设计的纵向模型测量了父母随着时间的推移酒精症状（DSM-IV）的数量。对于基因-环境的相互作用，我们将考虑一个童年虐待的回顾性措施。这项研究将使用正在进行的密歇根纵向研究（MLS）的数据进行，这是一项前瞻性社区确定的研究，涉及466个具有不同酗酒风险的家庭，已经持续了20多年（954名父母和1003名子女），每隔3年进行一次评估，每年在11岁至17岁之间进行评估。我们获得了密歇根大学的资助，从大卫戈德曼（NIAAA）设计的“成瘾小组”中对528个信息量最大的个体进行了1536个SNP（来自132个成瘾相关候选基因的1430个SNP和106个基因组对照SNP）的基因分型，使用了已在全国范围内用于分析成瘾相关性状的Illumina GoldenGate技术。由于该小组还包括SNP来衡量种族分层，它也将减轻对异质性的担忧。该提案的具体目标是：1）从参与行为特征（行为控制不足和消极情感特征）的5-羟色胺、多巴胺和GABA通路中识别增加酒精使用障碍（AUD）风险的遗传多态性。2)从这些相同的基因组中确定影响AUD严重程度进展的遗传变异。3)确定儿童期虐待是否与进展为AUD严重程度相关的遗传变异相互作用。这些基因的遗传变异可能会影响神经兴奋-抑制平衡，反过来可能会影响行为特征，从而增加发生AUD的风险，并与儿童虐待等环境因素相互作用。PI将获得基因-环境和基因-基因相互作用、纵向模型的统计方法方面的经验，并进一步加深她对行为风险因素的理解，以开发AUD。PI将能够将遗传专业知识添加到MLS研究组。 公共卫生关系：本研究旨在了解酒精使用障碍病因学中的遗传和环境风险以及保护因素。确定这些风险或保护因素将有助于更好地筛选易受伤害的受试者，改善风险评估，制定预防性干预措施，并促进适当的治疗。