Serotonin Genes and Adolescent Alcohol and Drug Involvement:Mechanisms of Risk

血清素基因与青少年酒精和药物参与：风险机制

• 批准号: 8713034
• 负责人: Frances L Wang
• 金额: $ 4.22万
• 依托单位: ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-21 至 2017-07-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713034
• 关键词: 10 year old; Accounting; Address; Adolescence; Adolescent; Adult; Alcohol Phenotype; Alcohol consumption; Alcohols; Anger; Anxiety; Arts; Attention deficit hyperactivity disorder; Bioinformatics; Biological; Candidate Disease Gene; Cessation of life; Characteristics; Child Development; Childhood; Communities; Comorbidity; DNA; Data; Data Set; Depressed mood; Development; Dimensions; Disease; Drug usage; Economics; Elements; Encyclopedia of DNA Elements; Etiology; Family; Gene Expression; Genes; Genetic; Genetic Research; Genetic Risk; Genomics; Genotype; HIV; Health; Heterogeneity; Injury; Link; Longitudinal Studies; Measures; Mediating; Mediator of activation protein; Mental Health; Meta-Analysis; Methods; Modeling; Outcome; Parents; Pathway interactions; Pharmaceutical Preparations; Phenotype; Play; Preventive Intervention; Psychopathology; Regulation; Risk; Risk Factors; Role; Sampling; Serotonin; Single Nucleotide Polymorphism; Smoking; Source; Symptoms; Techniques; Temperament; Testing; Variant; Violence; Youth; adolescent alcohol; base; biobank; conduct problem; depressive symptoms; economic cost; exome; high risk; improved; indexing; longitudinal design; physical conditioning; prospective; tool; trait

DESCRIPTION (provided by applicant): Alcohol and drug use increase the risk for violence, HIV, and injuries. Excessive alcohol use is a leading cause of preventable death, associated with over $200 billion in economic costs. Thus, it is a priority to understand the determinants of alcohol and drug use, particularly in youth. Low overall serotonergic (5-HT) functioning plays a role in the etiology of alcohol and drug involvement. However, the mechanisms underlying this relation are less clear as very few longitudinal studies on this topic have been conducted. Understanding the early mediating mechanisms in this relation would be informative for the etiology, prevention and intervention of alcohol and drug involvement. Measured genetic data can be leveraged to model variability in overall 5-HT function. Unfortunately, candidate gene studies have widely recognized limitations, including lack of replication, small effect sizes, and poor understanding of biological mechanisms. To address these gaps and limitations, the proposed study will prospectively examine childhood temperament characteristics and early adolescent psychopathology as potential mechanisms of influence in the relation between low overall serotonergic functioning and mid/late adolescent alcohol and drug involvement. It will test these models in two longitudinal studies of adolescents and will combine the results and account for heterogeneity across studies using meta-analytic techniques. Aim 1 will model genetic risk for low 5-HT function by using information from multiple single nucleotide polymorphisms (SNPs) to create a biologically based genetic risk score. SNPs in 5- HT genes will be selected for inclusion in the risk score by using bioinformatics tools, like the Encyclopeda of DNA Elements, to identify SNPs with functional effects on gene expression and/or regulation. Aim 2 will provide the first prospective test of childhood effortful control, sadness, and anger as moderated mediators in the relation between a genetic risk score indexing low 5-HT function and mid/late adolescent alcohol and drug involvement. Aim 3 will provide the first prospective test of early adolescent pure conduct problems (CP), pure depressive symptoms (DEP), and co-occurring CP/DEP as mediators in the relation between a genetic risk score indexing low 5-HT function and mid/late adolescent alcohol and drug involvement. Aim 3 will account for methodological limitations of previous studies by simultaneously accounting for art factual CP/DEP comorbidity and controlling for baseline alcohol/drug involvement and other adolescent psychopathology. The study has implications for understanding developmental pathways to alcohol and drug involvement and will be the first to prospectively study childhood temperament and early adolescent psychopathology as mechanisms of risk in the relation between a genetic risk score indexing low 5-HT function and alcohol and drug involvement in youth.

描述（由申请人提供）：酒精和吸毒增加了暴力，艾滋病毒和伤害的风险。过度使用饮酒是可预防死亡的主要原因，其经济成本超过2000亿美元。因此，了解酒精和吸毒的决定因素，尤其是在青年中是优先事项。低整体血清素能（5-HT）发挥作用在酒精和药物参与的病因中起作用。但是，这种关系的基础机制尚不清楚，因为很少进行有关该主题的纵向研究。了解这种关系中的早期介导机制将为酒精和药物参与的病因，预防和干预提供信息。可以利用测得的遗传数据来模拟整体5-HT功能的变异性。不幸的是，候选基因研究已被广泛认可的局限性，包括缺乏复制，小小的效应大小和对生物学机制的理解不佳。为了解决这些差距和局限性，拟议的研究将前瞻性地检查儿童的气质特征和早期的青少年心理病理学，这是潜在的影响力机​​制，在低整体血清素能功能与中/晚期的青少年酒精和药物参与之间的关系中。它将在两项青少年的纵向研究中测试这些模型，并将结果结合在一起，并考虑使用荟萃分析技术在整个研究中的异质性。 AIM 1通过使用来自多个单核苷酸多态性（SNP）的信息来建立低5-HT功能的遗传风险，以创建基于生物学的遗传风险评分。通过使用生物信息学工具（如DNA元素百科全书），将选择5-HT基因中的SNP以纳入风险评分，以识别对基因表达和/或调节功能效应的SNP。 AIM 2将对儿童期的第一个前瞻性测试进行努力控制，悲伤和愤怒，作为调解者，在遗传风险评分索引低5-HT功能与中/晚期青少年酒精和药物参与之间的关系中。 AIM 3将在青春期早期的纯粹行为问题（CP），纯抑郁症状（DEP）和同时发生的CP/DEP作为介体方面提供首次前瞻性测试，这是在遗传风险评分索引低5-HT功能与中/晚期青少年酒精和药物涉及的遗传风险分数之间的关系。 AIM 3将通过同时考虑艺术事实CP/DEP合并症以及控制基线酒精/药物参与和其他青少年心理病理学的方法来解释先前研究的方法论局限性。这项研究对了解酒精和药物参与的发育途径具有影响，并将成为前瞻性研究儿童气质和早期青少年心理病理学的遗传性风险机制，这是遗传风险评分索引低5-HT功能与酒精和药物参与的风险机制。