Genetic influences on alcoholism vulnerability in American Indians

美国印第安人的酗酒问题已在三个家庭关联数据集中得到解决：1个SW部落；2俄克拉何马东部部落酒精中毒患病率低；3平原印第安部落的神经心理学数据脑电图分析研究正在进行中，4十部落数据集。此外，LNG是首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。这项由S. O'Malley Yale领导的关于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延伸到美洲原住民（OMalley等人，2008）。这些项目包括通过半结构化精神病学访谈进行详细的精神病学评估，在酗酒流行程度不同的部落之间进行对比，研究等位基因和单倍型频率的跨种群变异，病例对照关联和家庭减数分裂连锁分析，检查个体差异在文化经验中的作用，以及——在其中两项研究中——广泛使用脑电图、ERP和心率变异性中间表型。最近，我们对精神分裂症（一种与酗酒有家族关系的疾病）在两个美洲印第安人群体中的报告，举例说明了对美洲印第安人与其他人群的精神病理学进行精神评估和比较的能力（Robin et al, 2007）。我们已经确定了几个候选基因的遗传变异，这些基因似乎改变了对酗酒的易感性或与酒精有关的特征，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，DRD2， HTR1B和Galanin。在最近的一项基因与环境相互作用的研究中，我们发现，在儿童时期遭受过性创伤的妇女酗酒和反社会人格的风险更高，但如果她们有低表达的MAOA基因型，那么这种风险就会更高，而MAOA基因型先前与行为控制障碍有关。对两个部落进行了全基因组扫描。第一项研究对西南印度一个家族（N=582）的517个STR基因座进行了基因分型，该家族在西南一个酗酒率高的部落中占相当大的比例（85%的男性，超过50%的女性）。SW部落基因组扫描检测到两个潜在的酗酒新位点：染色体11p端粒的DRD4区域和染色体4p着丝粒附近的GABAA簇区域。对Chr4上GABA受体簇区域的连锁热点进行高密度定位，发现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阵列基因型snp对平原印第安部落家族进行了全基因组扫描。我们发现的全基因组或重大或接近重大的发现详见AA000280-19报告。

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).