Gene-Environment Interations Underlying Alcoholism Vulnerability Disorders

酒精中毒脆弱性疾病背后的基因-环境相互作用

基本信息

批准号：
7963843
负责人：
David Goldman
金额：
$ 6.29万
依托单位：
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7963843
关键词：
7 year old 8 year old African American Age Alcohol abuse Alcoholism Alcohols Alleles American Indians Asians Behavior Birth Brain Catechol O-Methyltransferase Caucasians Caucasoid Race Child Child Sexual Abuse Childhood Cocaine DNA Data Dependence Development Disease Disinhibition Distal Environment Ethnic group Event Exons Exposure to Family General Population Genes Genetic Genetic Polymorphism Genotype Haplotypes Heroin Dependence Hyperactive behavior Individual Life Longitudinal Studies Monoamine Oxidase A Mothers Parents Patient Self-Report Pregnancy Psychiatry Questionnaires RNA Splicing Recruitment Activity Research Risk Risk Factors Sampling Stress Substance Addiction Suicide attempt Variant Woman Yin-Yang addiction anti social boys cohort depression experience externalizing behavior gene environment interaction girls maternal depression men pediatric trauma resilience serotonin transporter sex suicidal risk

项目摘要

Childhood adversity often pre-dates externalizing behaviors such as antisocial behavior and internalizing behaviors such as depression, both of which are risk factors for problem drinking and alcoholism. We have used data derived from parental self-report questionnaires in a birth cohort of approximately 7000 Caucasian girls and boys from the Avon Longitudinal Study of Parents and Children (ALSPAC), U.K. Mothers were recruited in early pregnancy and data is available on their children up to age 8 years. We have genotyped the children's DNA for functional polymorphisms in three genes: monoamine oxidase A (MAOA-LPR), serotonin transporter (5-HTTLPR) and catechol-O-methyltransferase (COMT Val158Met). In both sexes, exposure to family adversity and stressful life events in the first three years of life predicted behavioral disinhibition at age 4, persisting until at least age 7. In girls, MAOA-LPR interacted with stressful life events experienced from 6 months to 3.5 years to influence hyperactivity at ages 4 and 7. In boys, the interaction of MAOA-LPR with stressful life events between 1.5 and 2.5 years predicted hyperactivity at age 7 years. The low activity MAOA-LPR variant was associated with increased hyperactivity in girls and boys exposed to high stress. In contrast, there was no MAOA-LPR interaction with family adversity.(Enoch et al,in press, Genes Brain Behav). Maternal depression and stressful life events increased the odds of high emotionality in children but there were no main or interactive effects of COMT Val158Met (Evans et al, 2009) or 5-HTTLPR (Araya et al, 2009) on behavior. In the American Indian sample we found that the MAOA-LPR low activity allele was significantly associated with alcoholism, particularly antisocial alcoholism, only in women who had been exposed to childhood sexual abuse. In contrast, there was no relationship between alcoholism/antisocial behavior and MAOA-LPR genotype among non-abused women (Ducci et al, 2008). In the African American men we found that exposure to childhood trauma predicted substance dependence. Severe childhood trauma predicted polysubstance dependence. The African Americans had four common haplotypes within the distal GABRA2 haplotype block: two that correspond to the Caucasian and Asian yin-yang haplotypes and two not found in other ethnic groups. One of the unique GABRA2 haplotypes predicted heroin addiction whereas the other haplotype was more common in controls and appeared to confer resilience to addiction after exposure to severe childhood trauma. Furthermore, variation in an intronic GABRA2 SNP (rs11503014) that is putatively implicated in exon splicing interacted with childhood trauma to influence addiction vulnerability, particularly to cocaine (Enoch et al, in press, Biol Psychiatry). In another study in African American men and women, we found that haplotypes of FKBP5, a stress related gene, interacted with childhood trauma to predict suicide attempts: in the group exposed to high childhood adversity, 51% with two copies of the risk haplotype , 36% with one copy, and 20% with no copies had attempted suicide. In contrast, this haplotype conferred no suicide risk to individuals not exposed to childhood trauma (Roy et al, submitted).

儿童逆境通常会预先提前外部化行为，例如反社会行为和内在行为，例如抑郁症，这两者都是饮酒和酒精中毒的风险因素。我们已经使用了父母自我报告问卷得出的数据，其中包括大约7000名来自父母和子女的雅芳纵向研究（ALSPAC）的高加索男孩和男孩（ALSPAC），英国的母亲在怀孕初期被招募，并且数据可用于其儿童的数据。我们已经在三个基因的功能性多态性的儿童DNA中进行了基因分型：单胺氧化酶A（MAOA-LPR），5-羟色胺转运蛋白（5-HTTLPR）和Catechol-O-O-甲基转移酶（COMT VAL158MET）。在男女中，在生命的头三年中，暴露于家庭逆境和压力大的生活事件预测了4岁的行为抑制，至少直到至少7岁。在女孩中，Maoa-lpr与6个月至3.5岁的压力性生活事件相互作用，从而在4和7中影响了4和7年龄的人数。在男孩中，男孩的互动是在2.5岁的年龄段落中的2.5岁以上。5岁和2. 5年。低活性的MAOA-LPR变体与暴露于高压力的女孩和男孩的多动症增加有关。相反，与家庭逆境没有MAOA-LPR的相互作用。母体抑郁和压力性的生活事件增加了儿童的高情绪几率，但COMT Val158met（Evans等，2009）或5-HTTLPR（Araya等，2009）没有主要或互动效应。在美洲印第安人的样本中，我们发现MAOA-LPR低活动等位基因与酒精中毒，尤其是反社会酒精中毒，仅在暴露于儿童期性虐待的女性中。相反，非虐待妇女中酒精中毒/反社会行为与MAOA-LPR基因型之间没有关系（Ducci等，2008）。在非裔美国人中，我们发现暴露于儿童创伤会预测物质依赖。严重的童年创伤预测了多义依赖性。非洲裔美国人在远端Gabra2单倍型块中有四种常见的单倍型：两个与高加索和亚洲阳阳对应的单倍型，在其他种族中找不到两种。独特的Gabra2单倍型预测了海洛因成瘾，而另一种单倍型在对照中更为常见，并且在暴露于严重的儿童创伤后似乎赋予了成瘾的韧性。此外，内含子Gabra2 SNP（RS11503014）的变化被推论地与外显子剪接相互作用，与儿童创伤相互作用，以影响成瘾脆弱性，尤其是对可卡因（Enoch等人，在Press，Press，Biol Psychiatry中）。在非裔美国人男女的另一项研究中，我们发现FKBP5的单倍型是与压力相关的基因，与童年创伤相互作用以预测自杀尝试：在暴露于童年较高的较高的童年逆境中，有51％的风险单倍型，36％的副本，一份副本，没有副本，没有副本，而没有尝试过自杀。相比之下，这种单倍型不给未接触儿童创伤的人提供自杀风险（Roy等人，已提交）。