Genetic influences on alcoholism vulnerability in American Indians

遗传对美洲印第安人酗酒脆弱性的影响

基本信息

批准号：
7732112
负责人：
David Goldman
金额：
$ 79.04万
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/7732112
关键词：
11p Address Age Alaska Native Alcoholism Alcohols Alleles American Indians Antisocial Personality Disorder Anxiety Behavioral Benign COMT gene Candidate Disease Gene Catechol O-Methyltransferase Categories Centromere Child Chromosomes Clinical Communities Comorbidity Complex Connecticut DRD4 gene Data Data Set Development Diagnosis Disease Electroencephalography Environment Family Female Frequencies GABA Receptor Galanin Genes Genetic Genetic Variation Genome Genome Scan Genotype Haplotypes Heart Rate Heavy Drinking Impulsivity Indiana Indium Individual Differences Interview Laboratories Light Linkage Disequilibrium Low Prevalence Maps Mediating Meiosis Mental disorders Methaqualone Morbidity - disease rate Naltrexone Native Americans Oklahoma Pathology Pattern Pharmacogenetics Phenotype Population Prevalence Range Rate Receptor Gene Reporting Research Personnel Rest Risk Role SNP genotyping Scanning Schizophrenia Sertraline Signal Transduction Social Work Stress Structure Surveys Symptoms Trauma Tribes Universities Variant Violence Woman alcohol abuse therapy base binge drinker binge drinking biological adaptation to stress case control density drinking experience follow-up gamma-Aminobutyric Acid gene discovery gene environment interaction genetic linkage analysis genome wide association study male mortality neuropsychological problem drinker response telomere trait

项目摘要

The problem of alcoholism in American Indians has been addressed in three family linkage datasets: 1 SW tribe; 2 Eastern Oklahoma tribe with low prevalence of alcoholism; 3 Plains Indian tribe with neuropsychological data EEG - analytical studies in progress and 4 the Ten-Tribes dataset. In addition, LNG is the genetics collaborating laboratory on the first pharmacogenetic study on alcoholism treatment response to naltrexone and sertraline. This study on Alaska Natives, led by S. O'Malley Yale, recently showed that the efficacy of naltrexone in alcoholism treatment extends to Native Americans (OMalley et al, 2008). These projects include detailed psychiatric assessment with semi-structured psychiatric interviews, contrast between tribes differing in prevalence of alcoholism, study of cross-population variation in allele and haplotype frequencies, case-control association and family meiotic linkage analyses, examination of the role of individual differences in cultural experience, and - in two of the studies- the extensive use of EEG, ERP and heart rate variability intermediate phenotypes. The ability to psychiatrically assess and compare psychiatric pathology in American Indians with other populations was recently exemplified by our report on schizophrenia, a disease that is familially associated with alcoholism, in two American Indian populations (Robin et al, 2007). We have identified genetic variation in several candidate genes that appear to alter vulnerability to alcoholism or alcohol-related traits such as anxiety and impulsivity. These genes include COMT, the GABAA alpha 2 subunit and other GABAA receptor genes, DRD2, HTR1B and Galanin. In a recent gene x environment interaction study we showed that women who were sexually traumatized as children are at enhanced risk for alcoholism and antisocial personality, but much more so if they have the low expression MAOA genotype previously associated with behavioral dyscontrol. Whole genome scans were performed in two tribes. The first was conducted with 517 STR loci genotyped in a SW Indian family (N=582) that comprises a sizeable fraction of a Southwestern tribe with a high rate of alcoholism (85% of males, greater than 50% of females). The SW tribe genome scan detected two potential new loci for alcoholism: the DRD4 region at the chromosome 11p telomere, and the region of the GABAA cluster near the chromosome 4p centromere. The linkage hotspot in the GABA receptor cluster region on Chr4 was followed up with high density mapping, revealing a linkage disequilibrium signal at the GABA alpha 2 gene. This is in line with results from investigators at the University of Connecticut and the University of Indiana except that we were also able to show that the GABAA alpha 2 effect is apparently anxiety-mediated. A whole-genome scan using 5861 array-genotyped SNPs was performed on the Plains Indian tribal family. The genome-wide or significant or near-significant findings we have discovered are detailed in the report AA000280-19. In addition to gene discovery, we have also shed some light on the meaning and consequences of alcoholism in American Indians. The same patterns of psychiatric comorbidity seen in the general U.S. population National Comorbidity Survey are seen in Indian alcoholics, indicating that the diagnosis is capturing a similar set of clinical problems. Binge drinking in American Indians is neither benign nor beneficial. Almost all of the large fraction of SW Indians who were binge drink were also alcoholic, and binge drinkers tended to become alcoholic at a younger age. Regardless of whether binge drinkers met criteria for alcoholism, they were dramatically worse in each of four symptom categories evaluated in the SADS-L: social, work, violence/lawlessness and physical. These results help lay to rest the misconception that drinking, particularly binge-drinking, is other than deleterious to American Indians and regardless of whether binge drinking is culturally determined or congruent. Finally, stress/trauma - common in these communities and often a consequence of alcoholism and heavy alcohol use, was shown to be critically important risk element in the development of alcoholism and other psychiatric disorders. These findings, were originally reported from the SW Indian tribe, and then replicated in the Ten Tribes dataset (Yuan et al).

在三个家庭联系数据集中已经解决了美国印第安人的酒精中毒问题：1 SW部落； 2俄克拉荷马州的东部部落，酒精中毒患病率低； 3平原印度部落具有神经心理学数据脑电图 - 正在进行的分析研究和4个部落数据集。此外，液化天然气是遗传学合作实验室，该实验室在酒精中毒治疗对纳曲酮和舍曲林的反应的首次药物遗传学研究中。这项由S. O'Malley Yale领导的阿拉斯加原住民的研究最近表明，纳曲酮在酒精中毒治疗中的疗效扩展到美洲原住民（Omalley等，2008）。这些项目包括详细的精神病学评估以及半结构性的精神病访谈，酗酒流行率不同的部落之间的对比，研究等位基因和单倍型频率的跨种群变化的研究，病例对照频率，病例对照关联和家庭减数分裂联系分析，在文化经验中的作用以及两种范围的范围以及范围的范围 - 范围的范围 - 表型。我们的精神分裂症的报告最近体现了美洲印第安人与其他人群的精神病学评估和比较精神病病理学的能力，这是一种与酒精中毒有关的疾病，在两名美洲印第安人人口中与酒精中毒有关（Robin等人，2007年）。我们已经确定了几个候选基因的遗传变异，这些候选基因似乎改变了对酒精中毒或与酒精有关的特征（例如焦虑和冲动性）的脆弱性。这些基因包括COMT，GABAA Alpha 2亚基和其他GABAA受体基因，DRD2，HTR1B和Galanin。在最近的一项基因X环境互动研究中，我们表明，作为儿童进行性创伤的妇女具有增强酒精中毒和反社会人格的风险，但如果她们具有先前与行为障碍性相关的MAOA基因型低表达，则更多。整个基因组扫描是在两个部落进行的。第一个是在SW印度家族（n = 582）中使用的517 str基因座基因分型进行的，其中包括大量酒精中毒率（男性85％，女性大于50％）的西南部落的相当一部分。 SW部落的基因组扫描检测到了两个潜在的酒精中毒基因座：11p染色体染色体的DRD4区域，以及附近4p Centromere染色体的Gabaa簇区域。跟踪Chr4上GABA受体群集区域中的连锁热点，并进行高密度映射，揭示了GABA Alpha 2基因的连锁不平衡信号。这与康涅狄格大学和印第安纳大学的研究人员的结果一致，除了我们还能够证明Gabaa Alpha 2效应显然是焦虑介导的。使用5861阵列生成的SNP进行了全基因组扫描，在平原印度部落家族中进行。我们发现的全基因组或显着或近乎重要的发现在AA000280-19的报告中详细介绍了。除了发现基因外，我们还阐明了酒精中毒对美洲印第安人的含义和后果。在印度酒精中毒中，在美国总体合并症调查中观察到的精神病合并症的模式相同，这表明该诊断正在捕获类似的临床问题。美国印第安人的暴饮暴食既不是良性也不是有益的。几乎所有大量的狂饮印第安人都很酗酒，而暴饮暴食的人倾向于在年轻时变得酗酒。无论暴饮暴食者是否符合酒精中毒的标准，在SADS-L中评估的四个症状类别中的每一个中，他们都会变得越来越糟：社会，工作，暴力，暴力/无法实现和身体。这些结果有助于放弃误解，即饮酒，尤其是暴饮暴食，对美国印第安人来说是有害的，无论暴饮暴食是在文化上确定还是一致的。最后，压力/创伤 - 在这些社区中常见，通常是酒精中毒和大量饮酒的结果，被证明是酒精中毒和其他精神疾病的发展至关重要的风险因素。这些发现最初是从SW印度部落报告的，然后在十个部落数据集（Yuan等人）中进行了复制。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Validity of the SMAST in two American Indian tribal populations.

SMAST 在两个美洲印第安部落人群中的有效性。

DOI：
10.1081/ja-120030062
发表时间：
2004
期刊：
Substance use & misuse
影响因子：
2
作者：
Robin,RobertW;Saremi,Aramesh;Albaugh,Bernard;Hanson,RobertL;Williams,Desmond;Goldman,David
通讯作者：
Goldman,David

Haplotype-based linkage of tryptophan hydroxylase 2 to suicide attempt, major depression, and cerebrospinal fluid 5-hydroxyindoleacetic acid in 4 populations.

DOI：
10.1001/archpsyc.62.10.1109
发表时间：
2005-10
期刊：
Archives of general psychiatry
影响因子：
0
作者：
Zhifeng Zhou;A. Roy;Robert Lipsky;Kavi Kuchipudi;Guanshan Zhu;J. Taubman;M. Enoch;M. Virkkunen;D. Goldman
通讯作者：
Zhifeng Zhou;A. Roy;Robert Lipsky;Kavi Kuchipudi;Guanshan Zhu;J. Taubman;M. Enoch;M. Virkkunen;D. Goldman

Genetic factors and alcoholism.