Introduction: Special issue on genetic research of alcohol use disorder in diverse racial/ethnic populations

This special issue of The American Journal on Addictions is an extension of a workshop held at the Research Society on Alcoholism (2015) highlighting several important issues related to studies of the genetic bases of alcohol use disorder among racially/ethnically diverse populations. While not exhaustive in their coverage, the papers in this special issue focus on three important topics: (1) the importance of considering the social and environmental context in genetic analyses; (2) social and cultural considerations for engaging diverse communities in genetic research; and (3) methodologies related to phenotype development for use with racially/ethnically diverse populations. A brief overview of each paper included in these three sections is presented. The issue concludes with additional considerations for genetic research with racially/ethnically diverse population groups along with a commentary. (Am J Addict 2017;26:422–423

Ethnicity and Gender Comparisons of Health Consequences in Adults with Alcohol Dependence

The moderating effects of ethnicity and gender on factors associated with physical health consequences in adults with alcohol dependence was examined using data from the 2001–2002 U.S. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Black and White respondents with a lifetime diagnosis of DSM-IV alcohol dependence were selected for the study (n = 3,852). A multiple-group structural equation model tested ethnicity, gender, and intervening variables as predictors of physical health status in alcohol dependent men and women. Study findings offer implications for clinical practice with alcohol dependent individuals by identifying likely target groups and problems for intervention

Development and vulnerability factors in adolescent alcohol use

This article provides an overview of the characteristics of adolescent alcohol use, normative and subgroup variations in drinking behavior, and important factors associated with an increased risk for developing alcohol problems in later adolescence and young adulthood. A parental/family history of alcoholism, temperament traits, conduct problems, cognitive functioning, alcohol expectancies, and peer and other social relations are identified as influencing an adolescent’s susceptibility for initiating a variety of alcohol use behaviors. The Deviance Prone Model, proposed by Sher (1991), is presented as an important tool for testing possible relationships among the various risk factors and their sequencing that leads to early adolescent alcohol and drug initiation and use. It is also possible to extend the model to allow for an examination of the complex interplay of risk factors that leads to the development of alcohol use problems in late adolescence and young adults

Alcohol problems in young adults transitioning from adolescence to adulthood: The association with race and gender

Race and gender may be important considerations for recognizing alcohol related problems in Black and White young adults. This study examined the prevalence and age of onset of individual alcohol problems and alcohol problem severity across race and gender subgroups from a longitudinal study of a community sample of adolescents followed into young adulthood (N = 166; 23–29 yrs. old who were drinkers). All alcohol problems examined first occurred when subjects were in their late teens and early 20s. Drinking in hazardous situations, blackouts, and tolerance were the most common reported alcohol problems. In race and gender comparisons, more males than females experienced alcohol problems. Blacks generally had a later age of onset of alcohol problems. Multivariate regressions showed greater alcohol problem severity in males compared to females, but no significant differences between Blacks and Whites. Education, family environment and earlier alcohol use behaviors and expectancies were reliable predictors of alcohol problem severity in young adulthood. White males were at particular risk for experiencing more severe alcohol problems. Findings may inform the design of more targeted interventions for alcohol problems in different populations

Predictors of subgroups based on maximum drinks per occasion over six years for 833 adolescents and young adults in COGA.

ObjectiveA person's pattern of heavier drinking often changes over time, especially during the early drinking years, and reflects complex relationships among a wide range of characteristics. Optimal understanding of the predictors of drinking during times of change might come from studies of trajectories of alcohol intake rather than cross-sectional evaluations.MethodThe patterns of maximum drinks per occasion were evaluated every 2 years between the average ages of 18 and 24 years for 833 subjects from the Collaborative Study on the Genetics of Alcoholism. Latent class growth analysis identified latent classes for the trajectories of maximum drinks, and then logistic regression analyses highlighted variables that best predicted class membership.ResultsFour latent classes were found, including Class 1 (69%), with about 5 maximum drinks per occasion across time; Class 2 (15%), with about 9 drinks at baseline that increased to 18 across time; Class 3 (10%), who began with a maximum of 18 drinks per occasion but decreased to 9 over time; and Class 4 (6%), with a maximum of about 22 drinks across time. The most consistent predictors of higher drinking classes were female sex, a low baseline level of response to alcohol, externalizing characteristics, prior alcohol and tobacco use, and heavier drinking peers.ConclusionsFour trajectory classes were observed and were best predicted by a combination of items that reflected demography, substance use, level of response and externalizing phenotypes, and baseline environment and attitudes

A GABRA2 Polymorphism Improves a Model for Prediction of Drinking Initiation

Background Survival analysis was used to explore the addition of a single nucleotide polymorphism (SNP) and covariates (sex, interview age, and ancestry) on a previously published model's ability to predict onset of drinking. A SNP variant of rs279871, in the chromosome 4 gene encoding gamma-aminobutyric acid receptor (GABRA2), was selected due to its associations with alcoholism in young adults and with behaviors that increased risk for early drinking. Methods A subsample of 674 adolescents (ages 14–17) participating in the Collaborative Study on the Genetics of Alcoholism (COGA) was examined using a previously derived Cox proportional hazards model containing: 1) number of non-drinking related conduct disorder (CD) symptoms, 2) membership in a high-risk alcohol-dependent (AD) family, 3) most best friends drank (MBFD), 4) Achenbach Youth Self Report (YSR) externalizing score, and 5) YSR social problems score. The above covariates along with the SNP variant of GABRA2, rs279871, were added to this model. Five new prototype models were examined. The most parsimonious model was chosen based on likelihood ratio tests and model fit statistics. Results The final model contained four of the five original predictors (YSR social problems score was no longer significant and hence dropped from subsequent models), the three covariates, and a recessive GABRA2 rs279871 TT genotype (two copies of the high-risk allele containing thymine). The model indicated that adolescents with the high-risk TT genotype were more likely to begin drinking than those without this genotype. Conclusions The joint effect of the gene (rs279871 TT genotype) and environment (MBFD) on adolescent alcohol initiation is additive, but not interactive, after controlling for behavior problems (CD and YSR externalizing score). This suggests that the impact of the high-risk TT genotype on the onset of drinking is affected by controlling for peer drinking and does not include genotype-by-environment interactions

A Brief Critique of the TATES Procedure

The Trait-based test that uses the Extended Simes procedure (TATES) was developed as a method for conducting multivariate GWAS for correlated phenotypes whose underlying genetic architecture is complex. In this paper, we provide a brief methodological critique of the TATES method using simulated examples and a mathematical proof. Our simulated examples using correlated phenotypes show that the Type I error rate is higher than expected, and that more TATES p values fall outside of the confidence interval relative to expectation. Thus the method may result in systematic inflation when used with correlated phenotypes. In a mathematical proof we further demonstrate that the distribution of TATES p values deviates from expectation in a manner indicative of inflation. Our findings indicate the need for caution when using TATES for multivariate GWAS of correlated phenotypes

On the association of common and rare genetic variation influencing body mass index: a combined SNP and CNV analysis

Background As the architecture of complex traits incorporates a widening spectrum of genetic variation, analyses integrating common and rare variation are needed. Body mass index (BMI) represents a model trait, since common variation shows robust association but accounts for a fraction of the heritability. A combined analysis of single nucleotide polymorphisms (SNP) and copy number variation (CNV) was performed using 1850 European and 498 African-Americans from the Study of Addiction: Genetics and Environment. Genetic risk sum scores (GRSS) were constructed using 32 BMI-validated SNPs and aggregate-risk methods were compared: count versus weighted and proxy versus imputation. Results The weighted SNP-GRSS constructed from imputed probabilities of risk alleles performed best and was highly associated with BMI (p = 4.3×10−16) accounting for 3% of the phenotypic variance. In addition to BMI-validated SNPs, common and rare BMI/obesity-associated CNVs were identified from the literature. Of the 84 CNVs previously reported, only 21-kilobase deletions on 16p12.3 showed evidence for association with BMI (p = 0.003, frequency = 16.9%), with two CNVs nominally associated with class II obesity, 1p36.1 duplications (OR = 3.1, p = 0.009, frequency 1.2%) and 5q13.2 deletions (OR = 1.5, p = 0.048, frequency 7.7%). All other CNVs, individually and in aggregate, were not associated with BMI or obesity. The combined model, including covariates, SNP-GRSS, and 16p12.3 deletion accounted for 11.5% of phenotypic variance in BMI (3.2% from genetic effects). Models significantly predicted obesity classification with maximum discriminative ability for morbid-obesity (p = 3.15×10−18). Conclusion Results show that incorporating validated effect sizes and allelic probabilities improve prediction algorithms. Although rare-CNVs did not account for significant phenotypic variation, results provide a framework for integrated analyses

The Impact of Peer Substance Use and Polygenic Risk on Trajectories of Heavy Episodic Drinking Across Adolescence and Emerging Adulthood

BACKGROUND: Heavy episodic drinking is developmentally normative among adolescents and young adults, but is linked to adverse consequences in later life, such as drug and alcohol dependence. Genetic and peer influences are robust predictors of heavy episodic drinking in youth, but little is known about the interplay between polygenic risk and peer influences as they impact developmental patterns of heavy episodic drinking. METHODS: Data were from a multisite prospective study of alcohol use among adolescents and young adults with genome-wide association data (n = 412). Generalized linear mixed models were used to characterize the initial status and slopes of heavy episodic drinking between age 15 and 28. Polygenic risk scores (PRS) were derived from a separate genome-wide association study for alcohol dependence and examined for their interaction with substance use among the adolescents' closest friends in predicting the initial status and slopes of heavy episodic drinking. RESULTS: Close friend substance use was a robust predictor of adolescent heavy episodic drinking, even after controlling for parental knowledge and peer substance use in the school. PRS were predictive of the initial status and early patterns of heavy episodic drinking in males, but not in females. No interaction was detected between PRS and close friend substance use for heavy episodic drinking trajectories in either males or females. CONCLUSIONS: Although substance use among close friends and genetic influences play an important role in predicting heavy episodic drinking trajectories, particularly during the late adolescent to early adult years, we found no evidence of interaction between these influences after controlling for other social processes, such as parental knowledge and broader substance use among other peers outside of close friends. The use of longitudinal models and accounting for multiple social influences may be crucial for future studies focused on uncovering gene-environment interplay. Clinical implications are also discussed