Search

BACKGROUND AND AIMS: The associations between low educational attainment and substance use disorders (SUDs) may be related to a common genetic vulnerability. We aimed to elucidate the associations between polygenic scores for educational attainment and clinical criterion counts for three SUDs (alcohol, nicotine and cannabis). DESIGN: Polygenic association and sibling comparison methods. The latter strengthens inferences in observational research by controlling for confounding factors that differ between families. SETTING: Six sites in the United States. PARTICIPANTS: European ancestry participants aged 25 years and older from the Collaborative Study on the Genetics of Alcoholism (COGA). Polygenic association analyses included 5582 (54% female) participants. Sibling comparisons included 3098 (52% female) participants from 1226 sibling groups nested within the overall sample. MEASUREMENTS: Outcomes included criterion counts for DSM-5 alcohol use disorder (AUDSX), Fagerström nicotine dependence (NDSX) and DSM-5 cannabis use disorder (CUDSX). We derived polygenic scores for educational attainment (EduYears-GPS) using summary statistics from a large (> 1 million) genome-wide association study of educational attainment. FINDINGS: In polygenic association analyses, higher EduYears-GPS predicted lower AUDSX, NDSX and CUDSX [P

Background: Although trauma exposure (TE) is a transdiagnostic risk factor for many psychiatric disorders, not everyone who experiences TE develops a psychiatric disorder. Resilience may explain this heterogeneity; thus, it is critical to understand the etiologic underpinnings of resilience. Objective: The present study sought to examine the genetic underpinnings of psychiatric resilience using genome-wide association studies (GWAS), genome-wide complex trait analysis (GCTA), and polygenic risk score (PRS) analyses. Method: Participants were 6,634 trauma exposed college students attending a diverse, public university in the Mid Atlantic. GWAS and GCTA analyses were conducted, and using GWAS summary statistics from large genetic consortia, PRS analyses examined the shared genetic risk between resilience and various phenotypes. Results: Results demonstrate that nine single-nucleotide polymorphisms (SNPs) met the suggestive of significance threshold, heritability estimates for resilience were non-significant, and that there is genetic overlap between resilience and AD, as well as resilience and PTSD. Conclusion: Mixed findings from the present study suggest additional research to elucidate the etiological underpinnings of resilience, ideally with larger samples less biased by variables such as heterogeneity (i.e. clinical vs. population based) and population stratification. Genetic investigations of resilience have the potential to elucidate the molecular bases of stress-related psychopathology, suggesting new avenues for prevention and intervention efforts. Resilience may explain the heterogeneity in outcomes following trauma exposure; thus, it is critical to understand the etiologic underpinnings of resilience. The present study sought to examine the genetic underpinnings of psychiatric resilience using genome-wide association studies (GWAS), genome-wide complex trait analysis (GCTA), and polygenic risk score (PRS) analyses. Results demonstrated shared genetic overlap between resilience and Alcohol Dependence, as well as resilience and PTSD. Genetic investigations of resilience have the potential to elucidate the molecular bases of stress-related psychopathology, suggesting new avenues for prevention and intervention efforts. [ABSTRACT FROM AUTHOR]

Genetic factors contribute to the intergenerational transmission of alcohol misuse, but not all individuals at high genetic risk develop problems. The present study examined adolescent relationships with parents, peers, and romantic partners as predictors of realized resistance, defined as high biological risk for disorder combined with a healthy outcome, to alcohol initiation, heavy episodic drinking, and alcohol use disorder (AUD). Data were from the Collaborative Study on the Genetics of Alcoholism (N = 1,858; 49.9% female; mean age at baseline = 13.91 years). Genetic risk, indexed using family history density and polygenic risk scores for alcohol problems and AUD, was used to define alcohol resistance. Adolescent predictors included parent-child relationship quality, parental monitoring, peer drinking, romantic partner drinking, and social competence. There was little support for the hypothesis that social relationship factors would promote alcohol resistance, with the exception that higher father-child relationship quality was associated with higher resistance to alcohol initiation ( $$\hat \beta $$ = −0.19, 95% CI = −0.35, −0.03). Unexpectedly, social competence was associated with lower resistance to heavy episodic drinking ( $$\hat \beta $$ = 0.10, 95% CI = 0.01, 0.20). This pattern of largely null effects underscores how little is known about resistance processes among those at high genetic risk for AUD. [ABSTRACT FROM AUTHOR]

This study examined the independent and interactive effects of genetic risk for alcohol use disorder (AUD), parenting behaviors, and family environment on childhood impulsivity. Data were drawn from White (n = 5,991), Black/African American (n = 1,693), and Hispanic/Latino (n = 2,118) youth who completed the baseline assessment (age 9–10) and had genotypic data available from the Adolescent Brain Cognitive Development Study. Participants completed questionnaires and provided saliva or blood samples for genotyping. Results indicated no significant main effects of AUD genome-wide polygenic scores (AUD-PRS) on childhood impulsivity as measured by the UPPS-P scale across racial/ethnic groups. In general, parental monitoring and parental acceptance were associated with lower impulsivity; family conflict was associated with higher impulsivity. There was an interaction effect between AUD-PRS and family conflict, such that family conflict exacerbated the association between AUD-PRS and positive urgency, only among Black/African American youth. This was the only significant interaction effect detected from a total of 45 tests (five impulsivity dimensions, three subsamples, and three family factors), and thus may be a false positive and needs to be replicated. These findings highlight the important role of parenting behaviors and family conflict in relation to impulsivity among children. [ABSTRACT FROM AUTHOR]

Co-twin comparisons address familial confounding by controlling for genetic and environmental influences that twin siblings share. We applied the co-twin comparison design to investigate associations of adolescent factors with alcohol dependence (AD) symptoms. Participants were 1286 individuals (581 complete twin pairs; 42% monozygotic; and 54% female) from the FinnTwin12 study. Predictors included adolescent academic achievement, substance use, externalizing problems, internalizing problems, executive functioning, peer environment, physical health, relationship with parents, alcohol expectancies, life events, and pubertal development. The outcome was lifetime AD clinical criterion count, as measured in young adulthood. We examined associations of each adolescent domain with AD symptoms in individual-level and co-twin comparison analyses. In individual-level analyses, adolescents with higher levels of substance use, teacher-reported externalizing problems at age 12, externalizing problems at age 14, self- and co-twin-reported internalizing problems, peer deviance, and perceived difficulty of life events reported more symptoms of AD in young adulthood (ps < .044). Conversely, individuals with higher academic achievement, social adjustment, self-rated health, and parent-child relationship quality met fewer AD clinical criteria (ps < .024). Associations between adolescent substance use, teacher-reported externalizing problems, co-twin-reported internalizing problems, peer deviance, self-rated health, and AD symptoms were of a similar magnitude in co-twin comparisons. We replicated many well-known adolescent correlates of later alcohol problems, including academic achievement, substance use, externalizing and internalizing problems, self-rated health, and features of the peer environment and parent-child relationship. Furthermore, we demonstrate the utility of co-twin comparisons for understanding pathways to AD. Effect sizes corresponding to the associations between adolescent substance use, teacher-reported externalizing problems, co-twin-reported internalizing problems, peer deviance, and self-rated health were not significantly attenuated (p value threshold = .05) after controlling for genetic and environmental influences that twin siblings share, highlighting these factors as candidates for further research. [ABSTRACT FROM AUTHOR]

Background and aims: Research on adolescent predictors of later alcohol misuse is typically conducted on samples of singletons, and associations may be confounded by between‐family differences. To address potential confounding, we applied a co‐twin comparison design to evaluate whether differences between co‐twins in a wide array of adolescent risk factors predicted differences in young adult alcohol misuse. Design Longitudinal study in which associations between characteristics of the sample as adolescents were used to predict young adult alcohol misuse in individual‐level analyses and co‐twin comparisons. Setting: Finland. Participants: A total of 3402 individuals (1435 complete twin pairs; 36% monozygotic; 57% female) from the FinnTwin12 study. Measurements The young adult alcohol misuse outcome was a composite score of alcohol use and intoxication frequency. Adolescent predictors included factor scores representing academic performance, substance use, externalizing problems, internalizing problems, peer environment, physical health and relationship with parents; and single measures tapping alcohol expectancies, life events and pubertal development. Findings In individual‐level analyses, individuals with higher adolescent substance use, externalizing problems, time with friends, peer deviance, sports involvement, sleeping difficulties, parental discipline, positive alcohol expectancies and difficulty of life events reported higher alcohol misuse in young adulthood (Ps < 0.019, R2 = 0.0003–0.0310%). Conversely, those with higher adolescent internalizing problems, parent–child relationship quality and time with parents reported lower alcohol misuse (Ps < 0021, R2 = 0.0018–0.0093%). The associations with adolescent substance use and alcohol expectancies remained significant in co‐twin comparisons (Ps < 0.049, R2 = 0.0019–0.0314%). Further, academic performance emerged as a significant predictor, such that individuals with higher grades compared with their co‐twin reported higher young adult alcohol misuse (Ps < 0.029, R2 = 0.0449–0.0533%). Conclusions: Adolescent substance use, positive alcohol expectancies and higher academic performance appear to be robust predictors of later alcohol misuse. [ABSTRACT FROM AUTHOR]

Alcohol problems are influenced by both genetic and environmental factors. Evidence from twin models and measured gene-environment interaction studies has demonstrated that the importance of genetic influences changes as a function of the environment. Research has also shown that family-centered interventions may protect genetically susceptible youth from developing substance use problems. In this study, we brought large-scale gene identification findings into an intervention study to examine gene-by-intervention effects. Using genome-wide polygenic scores derived from an independent genome-wide association study of adult alcohol dependence, we examined whether an adolescent family-centered intervention would moderate the effect of genetic risk for alcohol dependence on lifetime alcohol dependence in young adulthood, approximately 15 years after the start of intervention, among European American (N = 271; 48.3% in the intervention condition) and African American individuals (N = 192; 51.6% in the intervention condition). We found that among European American individuals, the intervention moderated the association between alcohol dependence polygenic scores and lifetime alcohol dependence diagnosis in young adulthood. Among participants in the control condition, higher alcohol dependence polygenic scores were associated with a greater likelihood of receiving an alcohol dependence diagnosis; in contrast, among participants in the intervention condition, there was no association between alcohol dependence polygenic scores and alcohol dependence diagnosis. No moderation effect was found among African Americans. These results demonstrate that modifying environments of genetically vulnerable youth could reduce the likelihood of developing alcohol dependence and underscore the significance of environmentally focused prevention and intervention efforts. [ABSTRACT FROM AUTHOR]

Background: Characterizing aggregate genetic risk for alcohol misuse and identifying variants involved in gene‐by‐environment (G × E) interaction effects has so far been a major challenge. We hypothesized that functional genomic information could be used to enhance detection of polygenic signal underlying alcohol misuse and to prioritize identification of single nucleotide polymorphisms (SNPs) most likely to exhibit G × E effects. Methods: We examined these questions in the young adult FinnTwin12 sample (n = 1,170). We used genomewide association estimates from an independent sample to derive 2 types of polygenic scores for alcohol problems in FinnTwin12. Genomewide polygenic scores included all SNPs surpassing a designated p‐value threshold. DNase polygenic scores were a subset of the genomewide polygenic scores including only variants in DNase I hypersensitive sites (DHSs), which are open chromatin marks likely to index regions with a regulatory function. We conducted parallel analyses using height as a nonpsychiatric model phenotype to evaluate the consistency of effects. For the G × E analyses, we examined whether SNPs in DHSs were overrepresented among SNPs demonstrating significant G × E effects in an interaction between romantic relationship status and intoxication frequency. Results: Contrary to our expectations, we found that DNase polygenic scores were not more strongly predictive of alcohol problems than conventional polygenic scores. However, variants in DNase polygenic scores had per‐SNP effects that were up to 1.4 times larger than variants in conventional polygenic scores. This same pattern of effects was also observed in supplementary analyses with height. In G × E models, SNPs in DHSs were modestly overrepresented among SNPs with significant interaction effects for intoxication frequency. Conclusions: These findings highlight the potential utility of integrating functional genomic annotation information to increase the signal‐to‐noise ratio in polygenic scores and identify genetic variants that may be most susceptible to environmental modification. [ABSTRACT FROM AUTHOR]

Longitudinal analyses allow us to understand how genetic risk unfolds across development, in a way that is not possible with cross-sectional analyses of individuals at different ages. This has received little attention in genetic association analyses. In this study, we test for genetic effects of GABRA2, a gene previously associated with alcohol dependence, on trajectories of drunkenness from age 14 to 25. We use data from 1070 individuals who participated in the prospective sample of the Collaborative Study on the Genetics of Alcoholism, in order to better understand the unfolding of genetic risk across development. Piecewise linear growth models were fit to model the influence of genotype on rate of increase in drunkenness from early adolescence to young adulthood (14-18 years), the change in drunkenness during the transition to adulthood (18-19 years) and the rate of change in drunkenness across young adulthood (≥ 19 years). Variation in GABRA2 was associated with an increase in drunkenness that occurred at the transition between adolescence and adulthood. The genotypic effect was more pronounced in females. These analyses illustrate the importance of longitudinal data to characterize how genetic effects unfold across development. The findings suggest that transitions across important developmental periods may alter the relative importance of genetic effects on patterns of alcohol use. The findings also suggest the importance of considering gender when evaluating genetic effects on drinking patterns in males and females. [ABSTRACT FROM AUTHOR]

Background Very few studies chart developmental pathways from early childhood to adolescent alcohol-related outcomes. We test whether measures of temperament collected from mothers at multiple assessments from 6 months through 5 years predict alcohol-related outcomes in mid-adolescence, the developmental pathways that mediate these effects, and whether there are gender differences in pathways of risk. Methods Structural models were fit to longitudinal data from the Avon Longitudinal Study of Parents and Children, an epidemiological sample of pregnant women with delivery dates between April 1991 and December 1992, with children followed longitudinally. Temperamental characteristics were assessed at 6 time points from 6 to 69 months of age. Alcohol use and problems were assessed at age 15.5. Analyses here utilize data from 6,504 boys and 6,143 girls. Results Childhood temperament prior to age 5 predicted adolescent alcohol use and problems at age 15.5 years, even after controlling for socio-demographic factors and parental alcohol problems. In both boys and girls, 2 largely uncorrelated and distinct temperament styles-children who were rated as having consistent emotional and conduct difficulties through age 5, and children who were rated as consistently sociable through age 5-both showed elevated rates of alcohol problems at age 15.5, but via different mediational pathways. In both genders, the association between emotional and conduct difficulties and alcohol problems was mediated through reduced conscientiousness and lower emotional stability. The association between sociability and alcohol problems was mediated through increased extraversion and sensation-seeking for both genders. Boys also showed mediation for sociability and alcohol outcomes through friendship characteristics, and girls through lower conscientiousness and reduced emotional stability. Conclusions Our findings support multiple pathways to alcohol consumption and problems in adolescence. Some of these pathways are shared in boys and girls, while other risk factors are more salient in one gender or the other. [ABSTRACT FROM AUTHOR]

Background: Chromosome 7 has shown consistent evidence of linkage with a variety of phenotypes related to alcohol dependence in the Collaborative Study on the Genetics of Alcoholism (COGA) project. With a sample of 262 densely affected families, a peak logarithm of odds (LOD) score for alcohol dependence of 2.9 was observed at D7S1799. The LOD score in the region increased to 4.1 when a subset of the sample was genotyped with the Illumina Linkage III panel for the Genetic Analysis Workshop 14 (GAW14). To follow up on this linkage region, we systematically screened single nucleotide polymorphisms (SNPs) across a 2 LOD support interval surrounding the alcohol dependence peak. Methods: The SNPs were selected from the HapMap Phase I CEPH data to tag linkage disequilibrium bins across the region. Across the 18-Mb region, genotyped by the Center for Inherited Disease Research (CIDR), 1340 SNPs were analyzed. Family-based association analyses were performed on a sample of 1172 individuals from 217 Caucasian families. Results: Eight SNPs showed association with alcohol dependence at p < .01. Four of the eight most significant SNPs were located in or very near the ACN9 gene. We conducted additional genotyping across ACN9 and identified multiple variants with significant evidence of association with alcohol dependence. Conclusions: These analyses suggest that ACN9 is involved in the predisposition to alcohol dependence. Data from yeast suggest that ACN9 is involved in gluconeogenesis and the assimilation of ethanol or acetate into carbohydrate. [Copyright &y& Elsevier]

Background: There is an extensive and inconsistent literature on the association of the dopamine D2 receptor gene ( DRD2) with alcohol dependence. Conflicting results have been attributed to differences in the severity of the alcohol dependence phenotype across studies, failure to exclude related disorders from comparison groups, and artifacts of population-stratification. Recently the genetic polymorphism most widely analyzed in DRD2, Taq1A, has been discovered to reside in a neighboring gene, ankyrin repeat and kinase domain containing 1 ( ANKK1), located 10 kb downstream from DRD2. Methods: To more carefully characterize evidence for association across this region, we genotyped 26 single nucleotide polymorphisms (SNPs) spanning DRD2 and ANKK1 in a sample of 219 Caucasian families ( n = 1,923) from the Collaborative Study on the Genetics of Alcoholism (COGA), making this the most extensive analysis to date of association between this region and alcohol dependence. We used family-based analyses robust to population-stratification, and we made use of rich phenotypic data to analyze alcohol dependence and subtypes hypothesized in the literature to be more directly influenced by DRD2. Results: We found that the evidence for association is strongest in the 5′ linkage disequilibrium block of ANKK1 (that does not contain Taq1A), with weak evidence of association with a small number of SNPs in DRD2. The association in ANKK1 is strongest among the subsets of alcoholics with medical complications and with antisocial personality disorder. Conclusions: More extensive genotyping across DRD2 and ANKK1 suggests that the association with alcohol dependence observed in this region may be due to genetic variants in the ANKK1 gene. ANKK1 is involved in signal transduction pathways and is a plausible biological candidate for involvement in addictive disorders. [ABSTRACT FROM AUTHOR]

B Results: b For the EA subsample, we observed a significant main effect of PRS on AD symptoms ( = .15, p = .017), but no main effect of intervention condition on AD symptoms ( = .09, p = .113). There was a significant effect of PRS on AD symptoms for EA control participants ( = .181, p = .047) but not EA intervention participants ( = .121, p = .158). [Extracted from the article]

Highlights from the article: B Background: b Multimodal studies of brain function (neurophysiological, neuropsychological, neuroimaging) have identified specific functional and structural deficits in neural circuits (i.e., neural biomarkers) in individuals with alcohol use disorders (AUD) as well as those at risk-pointing to dysfunctional bottom-up reward processing, top-down inhibitory control networks, and interactions between cognitive, affective and frontal executive networks. B Results: b Preliminary evidence indicates that both alcohol use/problem and neurocognitive PRS predicted alcohol related neurocognitive functioning in COGA participants, with stronger associations observed for neurocognitive PRS (e.g., fluid intelligence PRS) than for alcohol related PRS (e.g., alcohol consumption and alcohol dependence PRS). B Discussion: b From this data, we can conclude that neural biomarkers can be used to further understanding of how genetic risk variants from large GWAS may relate to AUD and related behavior.