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. 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. 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 AA000280-18. ? 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.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Intramural Research (Z01)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Institute on Alcohol Abuse and Alcoholism
United States
Zip Code
Landefeld, Clare C; Hodgkinson, Colin A; Spagnolo, Primavera A et al. (2018) Effects on gene expression and behavior of untagged short tandem repeats: the case of arginine vasopressin receptor 1a (AVPR1a) and externalizing behaviors. Transl Psychiatry 8:72
Hong, L E; Yang, X; Wonodi, I et al. (2011) A CHRNA5 allele related to nicotine addiction and schizophrenia. Genes Brain Behav 10:530-5
O'Malley, Stephanie S; Robin, Robert W; Levenson, Aryeh L et al. (2008) Naltrexone alone and with sertraline for the treatment of alcohol dependence in Alaska natives and non-natives residing in rural settings: a randomized controlled trial. Alcohol Clin Exp Res 32:1271-83
Ducci, F; Enoch, M-A; Hodgkinson, C et al. (2008) Interaction between a functional MAOA locus and childhood sexual abuse predicts alcoholism and antisocial personality disorder in adult women. Mol Psychiatry 13:334-47
Robin, Robert W; Gottesman, Irving I; Albaugh, Bernard et al. (2007) Schizophrenia and psychotic symptoms in families of two American Indian tribes. BMC Psychiatry 7:30
Barnett, Jennifer H; Heron, Jon; Ring, Susan M et al. (2007) Gender-specific effects of the catechol-O-methyltransferase Val108/158Met polymorphism on cognitive function in children. Am J Psychiatry 164:142-9
Oquendo, Maria A; Hastings, Ramin S; Huang, Yung-Yu et al. (2007) Brain serotonin transporter binding in depressed patients with bipolar disorder using positron emission tomography. Arch Gen Psychiatry 64:201-8
Clarimon, Jordi; Gray, Rebecca R; Williams, Lindsey N et al. (2007) Linkage disequilibrium and association analysis of alpha-synuclein and alcohol and drug dependence in two American Indian populations. Alcohol Clin Exp Res 31:546-54
Minzenberg, Michael J; Xu, Ke; Mitropoulou, Vivian et al. (2006) Catechol-O-methyltransferase Val158Met genotype variation is associated with prefrontal-dependent task performance in schizotypal personality disorder patients and comparison groups. Psychiatr Genet 16:117-24
Enoch, Mary-Anne; Schwartz, Lori; Albaugh, Bernard et al. (2006) Dimensional anxiety mediates linkage of GABRA2 haplotypes with alcoholism. Am J Med Genet B Neuropsychiatr Genet 141:599-607

Showing the most recent 10 out of 34 publications