Bernard Albaugh

Dimensional anxiety mediates linkage of GABRA2 haplotypes with alcoholism

The GABAAα2 receptor gene (GABRA2) modulates anxiety and stress response. Three recent association studies implicate GABRA2 in alcoholism, however in these papers both common, opposite‐configuration haplotypes in the region distal to intron3 predict risk. We have now replicated the GABRA2 association with alcoholism in 331 Plains Indian men and women and 461 Finnish Caucasian men. Using a dimensional measure of anxiety, harm avoidance (HA), we also found that the association with alcoholism is mediated, or moderated, by anxiety. Nine SNPs were genotyped revealing two haplotype blocks. Within the previously implicated block 2 region, we identified the two common, opposite‐configuration risk haplotypes, A and B. Their frequencies differed markedly in Finns and Plains Indians. In both populations, most block 2 SNPs were significantly associated with alcoholism. The associations were due to increased frequencies of both homozygotes in alcoholics, indicating the possibility of alcoholic subtypes with opposite genotypes. Congruently, there was no significant haplotype association. Using HA as an indicator variable for anxiety, we found haplotype linkage to alcoholism with high and low dimensional anxiety, and to HA itself, in both populations. High HA alcoholics had the highest frequency of the more abundant haplotype (A in Finns, B in Plains Indians); low HA alcoholics had the highest frequency of the less abundant haplotype (B in Finns, A in Plains Indians) (Finns: P = 0.007, OR = 2.1, Plains Indians: P = 0.040, OR = 1.9). Non‐alcoholics had intermediate frequencies. Our results suggest that within the distal GABRA2 region is a functional locus or loci that may differ between populations but that alters risk for alcoholism via the mediating action of anxiety.

Common Genetic Origins for EEG, Alcoholism and Anxiety: The Role of CRH-BP

The resting EEG is a dynamic index of cortical activation, cognitive function and consciousness and is therefore an intermediate phenotype for many behaviors in which arousal is implicated such as anxiety and alcoholism. We performed a dense whole genome linkage scan using 3878 unlinked SNPs in a large pedigree derived from a population isolate sample of 328 Plains American Indians. Alpha (8–13 Hz), theta (4–8 Hz) and beta (13–30 Hz) EEG power was heritable (0.58–0.27) and stable over a 2 year period (r = 0.82–0.53). Genetic correlations between frequency bands were high (0.75). Linkage peaks for EEG power in all three frequency bands converged on chromosome 5q13-14 with genome-wide significant LOD scores of 3.5 (empirical p<0.0001) for alpha and beta power. A logical candidate gene, corticotropin releasing hormone-binding protein (CRH-BP), was located at the apex of these convergent linkage peaks. CRH-BP was significantly associated with alpha power in the Plains Indians and also in a replication sample of 188 Caucasians. Moreover, the same SNPs and haplotypes, located within the CRH-BP haplotype block, were also associated with anxiety disorders in the Plains Indians and alcohol use disorders in the Caucasians. CRH-BP modulates CRH which influences cortical and hippocampal EEG activity and is the primary mediator of the neuroendocrine stress response. Our results suggest a likely role for CRH-BP in stress-related alcoholism and highlight the use of the resting EEG as an intermediate phenotype for arousal-related behaviors such as anxiety and addiction.

GABRG1 and GABRA2 as independent predictors for alcoholism in two populations.

The chromosome 4 cluster of GABAA receptor genes is predominantly expressed in the brain reward circuitry and this chromosomal region has been implicated in linkage scans for alcoholism. Variation in one chromosome 4 gene, GABRA2, has been robustly associated with alcohol use disorders (AUD) although no functional locus has been identified. As HapMap data reveal moderate long-distance linkage disequilibrium across GABRA2 and the adjacent gene, GABRG1, it is possible that the functional locus is in GABRG1. We genotyped 24 SNPs across GABRG1 and GABRA2 in two population isolates: 547 Finnish Caucasian men (266 alcoholics) and 311 community-derived Plains Indian men and women (181 alcoholics). In both the Plains Indians and the Caucasians: (1) the GABRG1 haplotype block(s) did not extend to GABRA2; (2) GABRG1 haplotypes and SNPs were significantly associated with AUD; (3) there was no association between GABRA2 haplotypes and AUD; (4) there were several common (⩾0.05) haplotypes that spanned GABRG1 and GABRA2 (341 kb), three of which were present in both populations: one of these ancestral haplotypes was associated with AUD, the other two were more common in non-alcoholics; this association was determined by GABRG1; (5) in the Finns, three less common (<0.05) extended haplotypes showed an association with AUD that was determined by GABRA2. Our results suggest that there are likely to be independent, complex contributions from both GABRG1 and GABRA2 to alcoholism vulnerability.

Genome-wide association identifies candidate genes that influence the human electroencephalogram

Complex psychiatric disorders are resistant to whole-genome analysis due to genetic and etiological heterogeneity. Variation in resting electroencephalogram (EEG) is associated with common, complex psychiatric diseases including alcoholism, schizophrenia, and anxiety disorders, although not diagnostic for any of them. EEG traits for an individual are stable, variable between individuals, and moderately to highly heritable. Such intermediate phenotypes appear to be closer to underlying molecular processes than are clinical symptoms, and represent an alternative approach for the identification of genetic variation that underlies complex psychiatric disorders. We performed a whole-genome association study on alpha (α), beta (β), and theta (θ) EEG power in a Native American cohort of 322 individuals to take advantage of the genetic and environmental homogeneity of this population isolate. We identified three genes (SGIP1, ST6GALNAC3, and UGDH) with nominal association to variability of θ or α power. SGIP1 was estimated to account for 8.8% of variance in θ power, and this association was replicated in US Caucasians, where it accounted for 3.5% of the variance. Bayesian analysis of prior probability of association based upon earlier linkage to chromosome 1 and enrichment for vesicle-related transport proteins indicates that the association of SGIP1 with θ power is genuine. We also found association of SGIP1 with alcoholism, an effect that may be mediated via the same brain mechanisms accessed by θ EEG, and which also provides validation of the use of EEG as an endophenotype for alcoholism.

COMT Val158Met and cognition: main effects and interaction with educational attainment

Studies in children have shown that the genetic influence on cognition is positively correlated with socioeconomic status. Catechol‐O‐methyltransferase (COMT) Val158Met, a common, functional polymorphism, has been implicated in executive cognition and working memory. Imaging studies have shown that the variant Met allele is associated with more efficient prefrontal cortical processing and better attention but also emotional vulnerability to stress. We hypothesized that COMT Val158Met genotype would interact with years of education (yrs ed), one indicator of socioeconomic adversity, to predict cognitive task performance. We therefore administered the Wechsler Adult Intelligence Scale‐Revised (WAIS‐R) to 328 community‐derived, genotyped, Plains American Indians (mean yrs ed = 12; range = 5–18). We found significant genotypic effects on WAIS‐R measures of long‐term memory, working memory and attention. The Met allele was associated with improved performance in the Information and Picture Completion subscales; Met/Met homozygotes performed the best. COMT genotype interacted with yrs ed to influence Information and Block Design scores: Met allele carriers’ scores improved markedly with increasing yrs ed, whereas the scores of Val/Val individuals were only marginally influenced by yrs ed. There was a crossover of effects at 11–12 yrs ed: in the less educated group, Met allele carriers actually performed worse than Val/Val individuals perhaps because of emotional vulnerability to educational adversity, but in the better educated group, Met allele carriers excelled. Our study in Plains American Indians has shown that COMT Val158Met influences several aspects of cognition and some of its effects are moderated by educational adversity.

Alcoholism and Substance Sniffing among the Cheyenne and Arapaho Indians of Oklahoma

Common determinants of alcoholism and substance sniffing are identified among the Cheyenne and Arapaho Indians of Oklahoma. Computer correlations, interviews, and questionnaires provided data. Findings indicate chronic sniffing is prealcoholic behavior. Confusing family interpersonal relationships, alcoholism in the immediate family, and severe parent-child emotional deprivation predispose to alcoholism.

Use of the MMPI-2 in American Indians: I. Comparability of the MMPI-2 between two tribes and with the MMPI-2 normative group.

The comparability of the MMPI-2 in American Indians with the MMPI-2 normative group was investigated in a sample of 535 Southwestern and 297 Plains American Indian tribal members with contrasting sociocultural and historical origins. Both American Indian tribal groups had clinically significant higher T scores (> 5 T points) on 5 validity and clinical scales, 6 content scales, and 2 supplementary scales than did the MMPI-2 normative group. There were no significant differences between the 2 tribal groups on any of the MMPI-2 clinical, content, or supplementary scales. Matching members of both tribes with persons in the MMPI-2 normative group on the basis of age, gender, and education reduced the magnitude of the differences between the 2 groups on all of these scales, although the differences in T scores still exceeded 5 T points. It appears likely that the MMPI-2 differences of these 2 American Indian groups from the normative group may reflect their adverse historical, social, and economic conditions.

Use of the MMPI-2 in American Indians: II. Empirical correlates.

R. W. Robin, R. L. Greene, B. Albaugh, A. Caldwell, and D. Goldman (2003) reported that members of 2 American Indian tribal groups had statistically significant higher T scores on several MMPI-2 clinical, content, and supplementary scales than did the MMPI-2 normative group. The present study investigated the empirical correlates of the MMPI-2 scales in these American Indian tribal members. There were a large number of significant correlates reflecting antisocial symptoms with Scales 4 (Psychopathic Deviate), 9 (Hypomania), Anger, and Antisocial Practices. There were even a larger number of significant correlates reflecting generalized distress and negative affect with Scales 7 (Psychosthenia), 8 (Schizophrenia), Anxiety, Obsessions, Depression, and Welsh Anxiety. The rationally derived MMPI-2 content scales generally had larger correlations with these constructs than the clinical scales. Thus, the differences reported by R. W. Robin et al. (2003), appear to reflect behaviors and symptoms that American Indians participants were experiencing rather than test bias.

Validity of the SMAST in two American Indian tribal populations.

The standardized evaluation of alcoholism and other psychopathologies in minority populations, particularly American Indians, has long been questioned. This study investigated the validity of one of the most commonly applied assessments for alcoholism—the Short Michigan Alcohol Screening Test (SMAST)—in two distinct American Indian tribal groups. We analyzed data collected from 1989 to 1995 from largely community representative samples of 456 Southwestern and 214 Plains Indians ages 21 or older. For comparison, alcohol dependence was diagnosed using Diagnostic and Statistical Manual of Mental Disorders, Third Edition–Revised (DSM-III-R) criteria from a detailed, modified version of the Schedule for Affective Disorders and Schizophrenia—Lifetime (SADS-L). Accuracy of the SMAST was quantified as sensitivity, specificity, likelihood ratios, and the area under the curve for receiver operating characteristics, using the DSM-III-R diagnosis as the reference. The standard SMAST cutoff score of ≥3 had a demonstrated sensitivity 86% to 95%, but did not perform well in terms of specificity (23%–47%). Significantly higher cutoff scores (≥5 for both genders in the Southwestern tribe and 8 and ≥6 for men and women in the Plains tribe) were required to demonstrate acceptable levels of specificity in both tribes. The findings suggest that the SMAST is not a valid tool to screen for alcohol misuse in these two tribal populations. The highly elevated and different thresholds required from one population to the next and from one gender to the next constitute a significant obstacle to the use of the instrument.

Genetic and environmental risk factors for alcohol use disorders in American Indians and Alaskan Natives.

BACKGROUND AND OBJECTIVES Genetic and environmental predictors for alcohol use disorder (AUD) are both important in the general population. As a group, American Indian and Alaskan Native individuals (AI/AN) are at increased risk for alcohol-related morbidity /mortality, early onset problem drinking and AUD. METHODS Alcohol consumption behaviors amongst AI/AN tribes, environmental stressors and genetic studies in AI/AN and European-ancestry individuals are reviewed followed by an analysis of unique difficulties for undertaking research with AI/AN. RESULTS Some AI/AN tribes have high rates of childhood trauma that predict psychopathology including AUD. The deleterious effects of historical trauma and forced placement in boarding schools cross generations to the present day. There are scanty numbers of genetic studies of AUD in AI/AN and these derive from only a few tribes. However, it is important to note that the results are largely similar to findings in European-ancestry individuals indicating that AI/AN do not have increased genetic risk for AUD. Conducting AI/AN genetic studies has been challenging, in part because of tribe disillusionment and mistrust over past experiences and unique hurdles in getting consent from tribes, each a sovereign nation. However, it is encouraging that a new way forward has been established-community-based participatory research with tangible health benefits and a focus on strength-based approaches. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE Given the high prevalence of AUD in many AI/AN tribes and limited knowledge about genetic risk-resilience factors, it is important for our understanding of prevention and treatment that AI/AN research progresses and that more tribes are represented. (Am J Addict 2017;26:461-468).