Genetic influences on alcoholism vulnerability in American Indians

美洲印第安人的酗酒问题已经在三个家庭联系数据集中得到了解决：西南部落;酗酒流行率低的东部俄克拉荷马州部落;具有神经心理学数据的平原印第安部落EEG -正在进行的分析研究和十部落数据集。此外，LNG是第一个关于纳曲酮和舍曲林对酒精中毒治疗反应的药物遗传学研究的遗传学合作实验室。本研究以阿拉斯加原住民为研究对象，由S。O 'Malley Yale等人的研究表明，纳洛酮治疗酒精中毒的疗效延伸到美洲原住民（OMalley et al，2008）。这些项目包括详细的精神病评估与半结构化的精神病访谈，不同部落之间的对比，在酗酒的流行程度不同，研究跨人群的等位基因和单倍型频率的变化，病例对照协会和家庭减数分裂连锁分析，检查的作用，个人差异的文化经验，和-在两个研究-脑电图的广泛使用，ERP和心率变异性中间表型。最近，我们在两个美洲印第安人群体中对精神分裂症（一种与酗酒有家族关系的疾病）的报告举例说明了对美洲印第安人与其他群体的精神病理进行精神病学评估和比较的能力（Robin et al，2007）。我们已经确定了几个候选基因的遗传变异，这些基因似乎会改变对酒精中毒或酒精相关特征的易感性，如焦虑和冲动。这些基因包括COMT、GABAA α 2亚基和其他GABAA受体基因、DRD 2、HTR 1B和甘丙肽。在最近的一项基因x环境相互作用研究中，我们发现，儿童时期遭受性创伤的女性患酗酒和反社会人格的风险增加，但如果她们具有先前与行为失控相关的低表达MAOA基因型，则风险更大。在两个部落中进行了全基因组扫描。第一次进行了517个STR基因座基因分型的西南印度家庭（N=582），其中包括一个相当大的部分西南部落与酗酒率高（85%的男性，大于50%的女性）。SW部落基因组扫描检测到两个潜在的新的酗酒位点：染色体11 p端粒的DRD 4区域和染色体4p着丝粒附近的GABAA簇区域。在GABA受体簇区域的连锁热点的高密度定位，揭示了在GABA α 2基因的连锁不平衡信号。这与康涅狄格大学和印第安纳州大学的研究人员的结果一致，除了我们还能够证明GABAA α 2效应显然是焦虑介导的。使用5861个阵列基因分型SNP对平原印第安部落家族进行全基因组扫描（以诺等人，2008）。我们发现的全基因组或显著或接近显著的结果详见报告AA 000280 -19。在同一平原印第安人数据集的GWAS研究中，我们最近发现了几个与酒精中毒相关的静息EEG特征的全基因组显著位点（Hodgkinson et al，PNAS，2010）。 除了基因的发现，我们还揭示了美洲印第安人酗酒的意义和后果。在美国普通人群全国科摩罗调查中看到的精神病合并症模式与印度酗酒者相同，这表明诊断捕获了类似的临床问题。美洲印第安人的酗酒既不是良性的，也不是有益的。几乎所有的西南印第安人谁是酗酒的大部分也酗酒，酗酒者往往成为酗酒在年轻的时候。不管酗酒者是否符合酒精中毒的标准，他们在SADS-L中评估的四个症状类别中的每一个都明显更糟：社会，工作，暴力/无法无天和身体。这些结果有助于消除一种误解，即饮酒，特别是狂饮，对美洲印第安人有害，无论狂饮是文化决定的还是一致的。最后，压力/创伤-在这些社区很常见，往往是酗酒和大量饮酒的后果-被证明是酗酒和其他精神疾病发展的关键重要风险因素。这些发现最初来自西南印第安部落，然后在十个部落数据集中复制（Yuan等人）。

The problem of alcoholism in American Indians has been addressed in three family linkage datasets: SW tribe; Eastern Oklahoma tribe with low prevalence of alcoholism; Plains Indian tribe with neuropsychological data EEG - analytical studies in progress and 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, 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 (Enoch et al, 2008). The genome-wide or significant or near-significant findings we have discovered are detailed in the report AA000280-19. In a GWAS study in this same Plains Indian dataset, we recently found several genome-wide significant loci for alcoholism-associated resting EEG traits (Hodgkinson et al, PNAS, 2010). 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).