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 is associated with GALR3 but not two other galanin receptor genes.

The neuropeptide galanin is widely expressed in the periphery and the central nervous system and mediates diverse physiological processes and behaviors including alcohol abuse, depression and anxiety. Four genes encoding galanin and its receptors have been identified (GAL, GALR1, GALR2 and GALR3). Recently we found that GAL haplotypes were associated with alcoholism, raising the possibility that genetic variation in GALR1, GALR2 and GALR3 might also alter alcoholism risk. Tag single nucleotide polymorphisms (SNPs) were identified by genotyping SNP panels in controls from five populations. For the association study with alcoholism, six GALR1, four GALR2 and four GALR3 SNPs were genotyped in a large cohort of Finnish alcoholics and non-alcoholics. GALR3 showed a significant association with alcoholism that was driven by one SNP (rs3,091,367). Moreover, the combination of the GALR3 rs3,091,367 risk allele and GAL risk haplotypes led to a modestly increased odds ratio (OR) for alcoholism (2.4) as compared with the effect of either GAL (1.9) or GALR3 alone (1.4). Likewise, the combination of the GALR3 and GAL risk diplotypes led to an increased OR for alcoholism (4.6) as compared with the effect of either GAL (2.0) or GALR3 alone (1.6). There was no effect of GALR1 or GALR2 on alcoholism risk. This evidence suggests that GALR3 mediates the alcoholism-related actions of galanin.

Association of galanin haplotypes with alcoholism and anxiety in two ethnically distinct populations.

The neuropeptide galanin (GAL) is widely expressed in the central nervous system. Animal studies have implicated GAL in alcohol abuse and anxiety: chronic ethanol intake increases hypothalamic GAL mRNA; high levels of stress increase GAL release in the central amygdala. The coding sequence of the galanin gene, GAL, is highly conserved and a functional polymorphism has not yet been found. The aim of our study was, for the first time, to identify GAL haplotypes and investigate associations with alcoholism and anxiety. Seven single-nucleotide polymorphisms (SNPs) spanning GAL were genotyped in 65 controls from five populations: US and Finnish Caucasians, African Americans, Plains and Southwestern Indians. A single haplotype block with little evidence of historical recombination was observed for each population. Four tag SNPs were then genotyped in DSM-III-R lifetime alcoholics and nonalcoholics from two population isolates: 514 Finnish Caucasian men and 331 Plains Indian men and women. Tridimensional Personality Questionnaire harm avoidance (HA) scores, a dimensional measure of anxiety, were obtained. There was a haplotype association with alcoholism in both the Finnish (P=0.001) and Plains Indian (P=0.004) men. The SNPs were also significantly associated. Alcoholics were divided into high and low HA groups (>or= and

Neurocognitive impairment due to chronic alcohol consumption in an American Indian community.

OBJECTIVE: Studies have shown that clinically ascertained alcoholics tend to have lower scores than nonalcoholics on cognitive performance tests, particularly the Block Design (BD) and Digit Symbol (DS) tests of the Weschler Adult Intelligence Scale-Revised (WAIS-R). The aim of this study was to determine whether similar differences are found in a community sample of Plains Indian men and women with an episodic pattern of drinking and a high lifetime prevalence of alcoholism (71% for men, 44% for women). METHOD: We administered a truncated form of the WAIS-R to 334 members of a Plains Indian tribe (197 women and 137 men). Blind-rated psychiatric diagnoses were assigned according to Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III-R) criteria and based on the Schedule for Affective Disorders, Lifetime Version (SADS-L) interview. We compared 68 currently drinking alcoholics (38 men and 30 women), 116 abstaining alcoholics (59 men and 57 women) and 150 nonalcoholics (40 men and 110 women). RESULTS: Current and past heavy drinking had no impact on WAIS-R scores in women. Male alcoholics who were abstinent > or = 2years had similar scores to nonalcoholic men. Male current drinkers showed a trend for lower overall verbal and performance (PIQ) scores and BD performance subtest. Further analysis showed that drinking for > or = 15 years was significantly associated with reduced DS in male current drinkers. CONCLUSIONS: These findings suggest that for the men in this community sample, the impact on PIQ is due to the direct effect of chronic alcohol consumption on cognitive performance and is at least partially reversible after 2 years of abstinence.

Relationship of binge drinking to alcohol dependence, other psychiatric disorders, and behavioral problems in an American Indian tribe.

The hypothesis that binge drinking is a benign behavior not associated with alcohol dependence, other psychiatric disorders, or problem areas, in American Indians, was tested in a sample of 582 adult Southwestern American Indian males and females in large multigenerational pedigrees. All information was obtained from semistructured psychiatric interviews that were independently blind-rated for DSM-III-R diagnoses. Three main outcome measures were used: the relationship between binge drinking and (1) alcohol dependence and other psychiatric disorders, (2) substance abuse treatment, and (3) four behavioral problem categories-violence/lawlessness, physical, social, and work. Binge drinking and alcohol dependence were strongly associated. Most binge drinkers were diagnosed as alcohol dependent. However, when controlling for alcohol dependence and other covariates, binge drinking was independently associated with an increase in odds for positive diagnoses for multiple psychiatric disorders, and for social, work, physical, and violence/lawlessness behavioral problems. In sum, binge drinking was found to be a common and severe problem with deleterious consequences in multiple domains of functioning. Assessment instruments should be designed to elicit information on binge patterns of drinking and strategies devised to provide appropriate treatment.

Polymorphic admixture typing in human ethnic populations.

A panel of 257 RFLP loci was selected on the basis of high heterozygosity in Caucasian DNA surveys and equivalent spacing throughout the human genome. Probes from each locus were used in a Southern blot survey of allele frequency distribution for four human ethnic groups: Caucasian, African American, Asian (Chinese), and American Indian (Cheyenne). Nearly all RFLP loci were polymorphic in each group, albeit with a broad range of differing allele frequencies (delta). The distribution of frequency differences (delta values) was used for three purposes: (1) to provide estimates for genetic distance (differentiation) among these ethnic groups, (2) to revisit with a large data set the proportion of human genetic variation attributable to differentiation within ethnic groups, and (3) to identify loci with high delta values between recently admixed populations of use in mapping by admixture linkage disequilibrium (MALD). Although most markers display significant allele frequency differences between ethnic groups, the overall genetic distances between ethnic groups were small (.066-.098), and < 10% of the measured overall molecular genetic diversity in these human samples can be attributed to "racial" differentiation. The median delta values for pairwise comparisons between groups fell between .15 and .20, permitting identification of highly informative RFLP loci for MALD disease association studies.

DRD2 dopamine receptor genotype, linkage disequilibrium, and alcoholism in American Indians and other populations.

We defined interpopulation differences in the frequency of the dopamine D2 receptor DRD2/Taq1 A1 allele, which has previously been associated with alcoholism. Frequencies of the A1 allele in unrelated subjects were 0.18 to 0.20 (se = 0.02 to 0.03) in several Caucasian populations previously assessed, 0.38 (+/- 0.05) in American Blacks (n = 44), 0.63 (+/- 0.07) in Jemez Pueblo Indians (n = 23), and 0.80 (+/- 0.04) in Cheyenne Indians (n = 52). The existence of large interpopulation differences in the frequency of the Taq1 alleles suggests that associations to disease status could readily be generated or masked if disease and control groups were uneven in ethnic composition. To address the possibility that the 4-fold higher frequency of the A1 allele in Cheyenne Indians was related to an increased vulnerability to alcoholism in that population, 47 Cheyenne Indians were psychiatrically interviewed and blind-rated. However, there was no significant difference between interviewed controls (0.73 +/- 0.06, n = 24), subjects with alcoholism and/or drug abuse (0.74 +/- 0.06, n = 23) and noninterviewed population controls (0.87 +/- 0.05, n = 20). Legitimate association of the DRD2/Taq1 allele to alcoholism would presumably require it to be in linkage disequilibrium (nonrandom association) with a functional mutation at DRD2 or elsewhere. The level of disequilibrium would vary between populations and could place an upper bound on the strength of an association.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholism and substance abuse among selected southern Cheyenne Indians.

This family and small community-based study reports the occurrence of alcoholism and co-occurring substance abuse in Southern Cheyenne Indians living in western Oklahoma. Sociocultural factors complicate operationalization of clinical data into standard (DSM-III-R) psychiatric disorder terminology; understanding sociocultural factors is essential for assessing the high rate of addictive disorders in this group. To obtain reliable and valid clinical diagnoses, data from several sources were utilized within a blind rating system: 1) SADS-L, a clinician-administered research diagnostic instrument; 2) MAST; 3) relatives; 4) medical records; 5) other official documents. The sample consisted of 69 males (45 alcoholics) and 97 females (36 alcoholics). Among clinically significant substance abusers (moderate impairment of function), 22 of 24 were alcoholics. In non-alcoholics, mean MAST scores were 8.8 (males) and 5.1 (females); in alcoholics, 32.0 (males) and 38.7 (females). Mean age of onset on heavy use of alcohol was 20.1 yrs. (males) and 22.8 (females) (p = 0.047); among all alcoholics, 86% (males) and 64% (females) had early onset (< 25 yrs. old). When data from 98 unrelated subjects were analyzed separately, similar findings were observed except that mean age of onset of heavy use of alcohol was more discrepant between males and females, viz. 20.1 versus 22.8 yrs. (p = 0.02). Among those with substance abuse disorders, early age of onset was present in all but one female. In these Cheyenne, alcoholism is usually clinically severe and early in onset; it often co-occurs with substance abuse, also early in onset.

Factors associated with success among southern Cheyenne and Arapaho Indians.

Researchers in applied social science are seeking ways of approaching the facilitation of community-based development at the grass-roots level. Much research to date has focused on negative social aspects in communities, such as substance abuse and high numbers of school drop-outs. An innovative approach was developed that involved looking instead at successful individuals in communities. Individuals identified as successful were interviewed about the factors they associated with their own success. The experience of supportive parenting during their childhoods and moderation in alcohol and other substance use as adults were strongly correlated with success in life. The interview process provided an effective springboard for discussions and the development of intervention strategies at the community level.

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.