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Externalizing behavior in early adolescence is associated with alcohol use in adolescence and early adulthood and these behaviors often emerge as part of a developmental sequence. This pattern can be the result of heterotypic continuity, in which different behaviors emerge over time based on an underlying shared etiology. In particular, there is largely a shared genetic etiology underlying externalizing and substance use behaviors. We examined whether polygenic risk for alcohol use disorder predicted (1) externalizing behavior in early adolescence and alcohol use in adolescence in the Early Steps Multisite sample and (2) externalizing behavior in adolescence and alcohol use in early adulthood in the Project Alliance 1 (PAL1) sample. We examined associations separately for African Americans and European Americans. When examining European Americans in the Early Steps sample, greater polygenic risk was associated with externalizing behavior in early adolescence. In European Americans in PAL1, we found greater polygenic risk was associated with alcohol use in early adulthood. Effects were largely absent in African Americans in both samples. Results imply that genetic predisposition for alcohol use disorder may increase risk for externalizing and alcohol use as these behaviors emerge developmentally.

This study examined the independent and interactive effects of alcohol use disorder genome-wide polygenic scores (AUD-PGS) and parenting and family conflict on early adolescent externalizing behaviors. Data were drawn from White (N = 6181, 46.9% female), Black/African American (N = 1784, 50.1% female), and Hispanic/Latinx (N = 2410, 48.0% female) youth from the adolescent brain cognitive development Study (ABCD). Parents reported on youth externalizing behaviors at baseline (T1, age 9/10), 1-year (T2, age 10/11) and 2-year (T3, age 11/12) assessments. Youth reported on parenting and family environment at T1 and provided saliva or blood samples for genotyping. Results from latent growth models indicated that in general externalizing behaviors decreased from T1 to T3. Across all groups, higher family conflict was associated with more externalizing behaviors at T1, and we did not find significant associations between parental monitoring and early adolescent externalizing behaviors. Parental acceptance was associated with lower externalizing behaviors among White and Hispanic youth, but not among Black youth. Results indicated no significant main effect of AUD-PGS nor interaction effect between AUD-PGS and family variables on early adolescent externalizing behaviors. Post hoc exploratory analysis uncovered an interaction between AUD-PGS and parental acceptance such that AUD-PGS was positively associated with externalizing rule-breaking behaviors among Hispanic youth, but only when parental acceptance was very low. Findings highlight the important role of family conflict and parental acceptance in externalizing behaviors among early adolescents, and emphasize the need to examine other developmental pathways underlying genetic risk for AUD across diverse populations., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Parental divorce and discord are associated with poorer alcohol-related outcomes for offspring. However, not all children exposed to these stressors develop alcohol problems. Our objective was to test gene-by-environment interaction effects whereby children's genetic risk for alcohol problems modifies the effects of parental divorce and discord to predict alcohol outcomes., Methods: The sample included European (EA; N = 5608, 47% male, M age  ~ 36 years) and African (AA; N = 1714, 46% female, M age  ~ 33 years) ancestry participants from the Collaborative Study on the Genetics of Alcoholism. Outcomes included age at initiation of regular drinking and lifetime DSM-5 alcohol use disorder (AUD). Predictors included parental divorce, parental relationship discord, and offspring alcohol problems polygenic risk scores (PRS ALC ). Mixed effects Cox proportional hazard models were used to examine alcohol initiation and generalized linear mixed effects models were used to examine lifetime AUD. Tests of PRS moderation of the effects of parental divorce/relationship discord on alcohol outcomes were examined on multiplicative and additive scales., Results: Among EA participants, parental divorce, parental discord, and higher PRS ALC were associated with earlier alcohol initiation and greater lifetime AUD risk. Among AA participants, parental divorce was associated with earlier alcohol initiation and discord was associated with earlier initiation and AUD. PRS ALC was not associated with either. Parental divorce/discord and PRS ALC interacted on an additive scale in the EA sample, but no interactions were found in AA participants., Conclusions: Children's genetic risk for alcohol problems modifies the impact of parental divorce/discord, consistent with an additive model of diathesis-stress interaction, with some differences across ancestry., (© 2023 The Authors. Alcohol: Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol.)

We tested whether aspects of the childhood/adolescent home environment mediate genetic risk for alcohol problems within families across generations. Parental relationship discord and parental divorce were the focal environments examined. The sample included participants of European ancestry (N = 4806, 51% female) and African ancestry (N = 1960, 52% female) from the high-risk Collaborative Study on the Genetics of Alcoholism. Alcohol outcomes in the child generation included lifetime criterion counts for DSM-5 Alcohol Use Disorder (AUD), lifetime maximum drinks in 24 h, age at initiation of regular drinking, and age at first alcohol intoxication. Predictors in the parent generation included relationship discord, divorce, alcohol measures parallel to those in the child generation, and polygenic scores for alcohol problems. Parental polygenic scores were partitioned into alleles that were transmitted and non-transmitted to the child. The results from structural equation models were consistent with genetic nurture effects in European ancestry families. Exposure to parental relationship discord and parental divorce mediated, in part, the transmission of genetic risk for alcohol problems from parents to children to predict earlier ages regular drinking (β indirect  = -0.018 [-0.026, -0.011]) and intoxication (β indirect  = -0.015 [-0.023, -0.008]), greater lifetime maximum drinks (β indirect  = 0.006 [0.002, 0.01]) and more lifetime AUD criteria (β indirect  = 0.011 [0.006, 0.016]). In contrast, there was no evidence that parental alleles had indirect effects on offspring alcohol outcomes via parental relationship discord or divorce in the smaller number of families of African ancestry. In conclusion, parents transmit genetic risk for alcohol problems to their children not only directly, but also indirectly via genetically influenced aspects of the home environment. Further investigation of genetic nurture in non-European samples is needed., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

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 ( β ^ = - 0.19 , 95% CI = -0.35, -0.03). Unexpectedly, social competence was associated with lower resistance to heavy episodic drinking ( β ^ = 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., Competing Interests: Conflicts of interest. None.

Substance use disorders (SUDs) incur serious social and personal costs. The risk for SUDs is complex, with risk factors ranging from social conditions to individual genetic variation. We examined whether models that include a clinical/environmental risk index (CERI) and polygenic scores (PGS) are able to identify individuals at increased risk of SUD in young adulthood across four longitudinal cohorts for a combined sample of N = 15,134. Our analyses included participants of European (N EUR = 12,659) and African (N AFR = 2475) ancestries. SUD outcomes included: (1) alcohol dependence, (2) nicotine dependence; (3) drug dependence, and (4) any substance dependence. In the models containing the PGS and CERI, the CERI was associated with all three outcomes (ORs = 01.37-1.67). PGS for problematic alcohol use, externalizing, and smoking quantity were associated with alcohol dependence, drug dependence, and nicotine dependence, respectively (OR = 1.11-1.33). PGS for problematic alcohol use and externalizing were also associated with any substance dependence (ORs = 1.09-1.18). The full model explained 6-13% of the variance in SUDs. Those in the top 10% of CERI and PGS had relative risk ratios of 3.86-8.04 for each SUD relative to the bottom 90%. Overall, the combined measures of clinical, environmental, and genetic risk demonstrated modest ability to distinguish between affected and unaffected individuals in young adulthood. PGS were significant but added little in addition to the clinical/environmental risk index. Results from our analysis demonstrate there is still considerable work to be done before tools such as these are ready for clinical applications., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Drinking motives are robust proximal predictors of alcohol use behaviors and may mediate distinct etiological pathways in the development of alcohol misuse. However, little is known about the genetic and environmental etiology of drinking motives themselves and their potential utility as endophenotypes., Methods: Here, we leverage a longitudinal study of college students from diverse racial/ethnic backgrounds (phenotypic N = 9889, genotypic N = 4855) to investigate the temporal stability and demographic and environmental predictors of four types of drinking motives (enhancement, social, coping, and conformity). Using genome-wide association study (GWAS) and in silico tools, we characterize their associated genes and genetic variants (single nucleotide polymorphisms or SNPs)., Results: Drinking motives were stable across four years of college (ICC >0.74). Some robust environmental predictors of alcohol misuse (parental autonomy granting and peer deviance) were broadly associated with multiple types of drinking motives, while others (e.g., trauma exposure) were type specific. Genome-wide analyses indicated modest SNP-based heritability (14-22%, n.s.) and several suggestive genomic loci that corroborate findings from previous molecular genetic studies (e.g., PECR and SIRT4 genes), indicating possible differences in the genetic etiology of positive versus negative reinforcement drinking motives that align with an internalizing/externalizing typology of alcohol misuse. Coping motives were significantly genetically correlated with alcohol use disorder diagnoses (r g  = 0.71, p = 0.001). However, results from the genetic analyses were largely underpowered to detect significant associations., Conclusions: Drinking motives show promise as endophenotypes but require further investigation in larger samples to further our understanding of the etiology of alcohol misuse., (© 2022 The Authors. Alcoholism: Clinical & Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcoholism.)

Background: Individual variation in the physiological response to alcohol is predictive of an individual's likelihood to develop alcohol use disorder (AUD). Evidence from diverse model organisms indicates that the levels of long-chain polyunsaturated omega-3 fatty acids (ω-3 LC-PUFAs) can modulate the behavioral response to ethanol and therefore may impact the propensity to develop AUD. While most ω-3 LC-PUFAs come from diet, humans can produce these fatty acids from shorter chain precursors through a series of enzymatic steps. Natural variation in the genes encoding these enzymes has been shown to affect ω-3 LC-PUFA levels. We hypothesized that variation in these genes could contribute to the susceptibility to develop AUD., Methods: We identified nine genes (FADS1, FADS2, FADS3, ELOVL2, GCKR, ELOVL1, ACOX1, APOE, and PPARA) that are required to generate ω-3 LC-PUFAs and/or have been shown or predicted to affect ω-3 LC-PUFA levels. Using both set-based and gene-based analyses we examined their association with AUD and two AUD-related phenotypes, alcohol consumption, and an externalizing phenotype., Results: We found that the set of nine genes is associated with all three phenotypes. When examined individually, GCKR, FADS2, and ACOX1 showed significant association signals with alcohol consumption. GCKR was significantly associated with AUD. ELOVL1 and APOE were associated with externalizing., Conclusions: Taken together with observations that dietary ω-3 LC-PUFAs can affect ethanol-related phenotypes, this work suggests that these fatty acids provide a link between the environmental and genetic influences on the risk of developing AUD., (© 2022 The Authors. Alcoholism: Clinical & Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcoholism.)

In this study, we test principal component analysis (PCA) of measured confounders as a method to reduce collider bias in polygenic association models. We present results from simulations and application of the method in the Collaborative Study of the Genetics of Alcoholism (COGA) sample with a polygenic score for alcohol problems, DSM-5 alcohol use disorder as the target phenotype, and two collider variables: tobacco use and educational attainment. Simulation results suggest that assumptions regarding the correlation structure and availability of measured confounders are complementary, such that meeting one assumption relaxes the other. Application of the method in COGA shows that PC covariates reduce collider bias when tobacco use is used as the collider variable. Application of this method may improve PRS effect size estimation in some cases by reducing the effect of collider bias, making efficient use of data resources that are available in many studies., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To examine associations between alcohol use disorder (AUD), its psychiatric comorbidities, and their interactions, with marital outcomes in a diverse high-risk, genetically informative sample., Method: Participants included European ancestry (EA; n = 4,045) and African ancestry (AA; n = 1,550) individuals from the multigenerational Collaborative Study on the Genetics of Alcoholism (COGA) sample (56% female, M age ∼ 41 years). Outcomes were lifetime marriage and divorce. Predictors included lifetime AUD, an alcohol problems polygenic score (PRS), and AUD comorbidities, including conduct or antisocial personality disorder (ASP), cannabis dependence/abuse (CAN), frequent tobacco use (TOB), and major depressive disorder (MDD). Mixed effect Cox models and generalized linear mixed effects models were fit., Results: Among EA participants, those with AUD and CAN were less likely to marry (hazard ratios [HRs] 0.70-0.83, p s < 0.01). Among AA participants, those with AUD and TOB were less likely to marry (HRs 0.66-0.82, p s < 0.05) and those with MDD were more likely to marry (HR = 1.34, p s < 0.01). Among EA participants, AUD, CAN, TOB, and MDD were associated with higher odds of divorce (odds ratios [ORs] 1.59-2.21, p s < 0.01). Among AA participants, no predictors were significantly associated with divorce. Significant random effects indicated genetic and environmental influences on marriage, but only environmental factors on divorce., Conclusions: In a high-risk sample, AUD was associated with reduced likelihood of marriage in EA and AA individuals and increased risk of divorce in EA individuals. These associations were largely independent of comorbidities. Genetic and environmental background factors contributed to marriage, while only environmental background factors contributed to divorce. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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.

Genetic predispositions play an important role in alcohol use. Understanding the psychosocial mechanisms through which genetic risk unfolds to influence alcohol use outcomes is critical for identifying modifiable targets and developing prevention and intervention efforts. In this study, we examined the role of sensation seeking and social support from family and friends in linking genetic risk to alcohol use. We also examined the role of social support in moderating the associations between genetic risk and sensation seeking and alcohol use. Data were drawn from a sample of 2,836 European American adults from the Collaborative Study on the Genetics of Alcoholism (46% male, mean age = 35.65, standard deviation [ SD ] = 10.78). Results from path analysis indicated that genome-wide polygenic scores for alcohol consumption (alc-GPS) were associated with higher sensation seeking, which in turn was associated with higher levels of alcohol use. alc-GPS was also associated with higher alcohol use indirectly via lower levels of family support. In addition, high friend support attenuated the association between alc-GPS and sensation seeking and alcohol use. The pattern of associations was similar for males and females, with some differences in the associations between social support and alcohol use observed across age. Our findings highlight the important role of intermediate phenotypes and gene-environment interplay in the pathways of risk from genetic predispositions to complex alcohol use outcomes. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Predictive models for recovering from alcohol use disorder (AUD) and identifying related predisposition biomarkers can have a tremendous impact on addiction treatment outcomes and cost reduction. Our sample (N = 1376) included individuals of European (EA) and African (AA) ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA) who were initially assessed as having AUD (DSM-5) and reassessed years later as either having AUD or in remission. To predict this difference in AUD recovery status, we analyzed the initial data using multimodal, multi-features machine learning applications including EEG source-level functional brain connectivity, Polygenic Risk Scores (PRS), medications, and demographic information. Sex and ancestry age-matched stratified analyses were performed with supervised linear Support Vector Machine application and were calculated twice, once when the ancestry was defined by self-report and once defined by genetic data. Multifeatured prediction models achieved higher accuracy scores than models based on a single domain and higher scores in male models when the ancestry was based on genetic data. The AA male group model with PRS, EEG functional connectivity, marital and employment status features achieved the highest accuracy of 86.04%. Several discriminative features were identified, including collections of PRS related to neuroticism, depression, aggression, years of education, and alcohol consumption phenotypes. Other discriminated features included being married, employed, medication, lower default mode network and fusiform connectivity, and higher insula connectivity. Results highlight the importance of increasing genetic homogeneity of analyzed groups, identifying sex, and ancestry-specific features to increase prediction scores revealing biomarkers related to AUD remission.

Previous research suggests that genetic risk factors may predispose to conduct problems and alcohol use in adolescence. Whether genetic risk factors interact with social contexts has not been well characterized among African American adolescents. Data came from a subsample of the Genes, Environment, and Neighborhood Initiative study comprising 501 African American adolescents, including 151 lifetime drinkers (56% female, mean age = 16.3, SD = 1.4). Genetic risk was assessed with polygenic risk scores for alcohol dependence. Analyses explored interactions between genetic risk and self-reported alcohol use, conduct problems, life stressors, and other covariates. The effects of two gene-environment interactions (G × E) were tested in the sample of alcohol exposed adolescents; one on conduct problems and the other on alcohol use. There were significant associations between polygenic risk for alcohol dependence and conduct problems. A significant G × E interaction showed the impact of genetic risk on conduct problems was stronger under conditions of high exposure to family and neighborhood stressors. Among this sample of African American adolescents, genetic risk for alcohol dependence was not directly associated with alcohol use but was related to more conduct problems. Further, the effect of genetic risk interacted with stressors from the family and neighborhood, so that the effect of genetic risk on conduct problems was stronger for individuals who reported greater stressors.

Genome-wide, polygenic risk scores (PRS) have emerged as a useful way to characterize genetic liability. There is growing evidence that PRS may prove useful for early identification of those at increased risk for certain diseases. The current potential of PRS for alcohol use disorders (AUD) remains an open question. Using data from both a population-based sample [the FinnTwin12 (FT12) study] and a high-risk sample [the Collaborative Study on the Genetics of Alcoholism (COGA)], we examined the association between PRSs derived from genome-wide association studies (GWASs) of (1) alcohol dependence/alcohol problems, (2) alcohol consumption, and (3) risky behaviors with AUD and other substance use disorder (SUD) criteria. These PRSs explain ~2.5-3.5% of the variance in AUD (across FT12 and COGA) when all PRSs are included in the same model. Calculations of area under the curve (AUC) show PRS provide only a slight improvement over a model with age, sex, and ancestral principal components as covariates. While individuals in the top 20, 10, and 5% of the PRS distribution had greater odds of having an AUD compared to the lower end of the continuum in both COGA and FT12, the point estimates at each threshold were statistically indistinguishable. Those in the top 5% reported greater levels of licit (alcohol and nicotine) and illicit (cannabis and opioid) SUD criteria. PRSs are associated with risk for SUD in independent samples. However, usefulness for identifying those at increased risk in their current form is modest, at best. Improvement in predictive ability will likely be dependent on increasing the size of well-phenotyped discovery samples.

Background: we aimed to determine the risk factors and associated population attributable fractions (PAFs) for the age of onset of alcohol use and also to identify protective factors., Methods: we analyzed follow-up data collected between autumn 2011 and spring 2016 ( n = 5170) from the first two cohorts (2011, 2012) of the Spit for Science TM project. The dependent variables were alcohol abuse and dependence, and the independent variables were age of drinking onset, residence, ethnicity, religiosity, sexual orientation and work status. We determined the odds ratios (OR) using multilevel logistic regression for repeated measures in SPSSv.20., Results: the early onset of alcohol use was associated with an increased risk of alcohol abuse and dependence among females (OR = 14.98; OR = 11.83) and males (OR = 7.41; OR = 6.24). The PAFs for the early onset of alcohol use in alcohol abuse and dependence were respectively 80.9% and 71.7% in females and 71.0% and 63.5% in males. Among females, being white (OR = 1.58; OR = 1.51), living off-campus (OR = 1.73; OR = 2.76) and working full-time (OR = 1.69; OR = 1.78) were also risk factors. Strong religious beliefs were found to protect males from alcohol abuse (OR = 0.58), while same-gender sexual orientation increased the risk among females (OR = 2.09)., Conclusion: delaying the age of onset by one year would reduce alcohol abuse among young adults.

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 < 0.01, effect sizes (R 2 ) ranging from 0.30 to 1.84%]. These effects were robust in sibling comparisons, where sibling differences in EduYears-GPS predicted all three SUDs (P < 0.05, R 2 0.13-0.20%)., Conclusions: Individuals who carry more alleles associated with educational attainment tend to meet fewer clinical criteria for alcohol, nicotine and cannabis use disorders, and these effects are robust to rigorous controls for potentially confounding factors that differ between families (e.g. socio-economic status, urban-rural residency and parental education)., (© 2019 Society for the Study of Addiction.)

Background and Aims: Previous twin research suggests relationship status can moderate underlying genetic liability towards alcohol misuse. This paper examined: (1) whether genome-wide polygenic scores (GPS) for alcohol consumption are associated with alcohol misuse; (2) whether these GPS are moderated by romantic relationships (gene-environment interaction; G × E) and (3) whether G × E results are consistent across sex., Design: Linear mixed-effects models were used to test associations between genome-wide polygenic scores, relationship status and alcohol use/misuse., Setting: Finnish twins born between 1983 and 1987 identified through Finland's central population registry., Participants: An intensively studied subset of Finnish Twin Study (FinnTwin12) during the young adult phase (aged 20-26 years). The analytical sample includes those with complete interview and genetic data (n = 1201)., Measurements: Key measurements included involvement in a romantic partnership, drinking frequency, intoxication frequency and DSM-IV alcohol dependence (AD) symptoms. Genome-wide polygenic scores (GPS) were created from available summary statistics from a large genome-wide association study (GWAS) of drinks per week., Results: GPS predicted drinking frequency [b = 0.109; 95% confidence interval (CI) = 0.050, 0.168], intoxication frequency (b = 0.111; 95% CI = 0.054, 0.168) and AD symptoms (b = 0.123; 95% CI = 0.064, 0.182). Having a romantic relationship negatively influenced the association between GPS and drinking frequency (b = -0.105; 95% CI = -0.211, -0.001), intoxication frequency (b = -0.118; 95% CI = -0.220, -0.016) and AD symptoms (b = -0.119; 95% CI = -0.229, -0.009). There was a three-way interaction between sex, relationship status and GPS for intoxication frequency (b = 0.223; 95% CI = 0.013, 0.433), such that the reduced association between GPS and intoxication frequency for those in a relationship was only apparent in males. We found no evidence of three-way interactions for drinking frequency or AD symptoms., Conclusions: Being in a romantic relationship reduced the association between genetic predisposition and drinking, high-risk drinking and alcohol problems. However, for high-risk drinking the protective effect was limited to males, mapping onto earlier findings suggesting that males benefit more from romantic partnerships., (© 2019 Society for the Study of Addiction.)

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.

Background: The period of college represents a particularly risky developmental stage with regard to alcohol use, as college students engage in more risky drinking behaviors than their noncollege peers, and such problematic alcohol use is associated with far-reaching negative consequences. Existing findings from genome-wide association studies (GWAS) indicate that alcohol consumption has a complex polygenic etiology. Currently, there is a lack of studies examining genetic risk for alcohol consumption using polygenic risk scores (PRS) in college samples. In this study, we examined whether alcohol-specific and risky behavior-related PRS were longitudinally associated with alcohol consumption among college students and whether this effect might be partially mediated by impulsivity domains., Methods: The sample included n = 2,385 European ancestry (EA) and n = 1,153 African ancestry (AA) college students assessed over the course of 4 years. To indicate genetic risk, 2 PRS were created based on recent large-scale GWAS: alcohol consumption (Liu et al., 2019) -drinks per week (DPW)-PRS and risky behaviors (Linnér et al., 2019) -RISK-PRS. The main outcome was alcohol consumption, measured across 4 waves of follow-up data. The UPPS-P impulsivity subscales were examined as mediators of the genetic effect on alcohol consumption., Results: The results from structural equation modeling showed that among EA students, both DPW-PRS and RISK-PRS had significant positive effects on alcohol consumption above and beyond UPPS dimensions and control variables. RISK-PRS explained larger portion of variance in alcohol consumption than DPW-PRS. RISK-PRS showed a significant indirect effect on alcohol consumption through sensation seeking and lack of perseverance; no significant indirect effect of DPW-PRS was found. No significant association of either PRS or alcohol consumption was found for AA participants., Conclusions: The current results found that PRS related to more broadly defined risky behaviors predicted alcohol consumption across college years and that this association was partially mediated via dimensions of impulsivity., (© 2019 by the Research Society on Alcoholism.)

Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10 -13 ) and African ancestries (rs2066702; P = 2.2 × 10 -9 ). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

Understanding how ethanol actions on brain signal transduction and gene expression lead to excessive consumption and addiction could identify new treatments for alcohol dependence. We previously identified glycogen synthase kinase 3-beta (Gsk3b) as a member of a highly ethanol-responsive gene network in mouse medial prefrontal cortex (mPFC). Gsk3b has been implicated in dendritic function, synaptic plasticity and behavioral responses to other drugs of abuse. Here, we investigate Gsk3b in rodent models of ethanol consumption and as a risk factor for human alcohol dependence. Stereotactic viral vector gene delivery overexpression of Gsk3b in mouse mPFC increased 2-bottle choice ethanol consumption, which was blocked by lithium, a known GSK3B inhibitor. Further, Gsk3b overexpression increased anxiety-like behavior following abstinence from ethanol. Protein or mRNA expression studies following Gsk3b over-expression identified synaptojanin 2, brain-derived neurotrophic factor and the neuropeptide Y Y5 receptor as potential downstream factors altering ethanol behaviors. Rat operant studies showed that selective pharmacologic inhibition of GSK3B with TDZD-8 dose-dependently decreased motivation to self-administer ethanol and sucrose and selectively blocked ethanol relapse-like behavior. In set-based and gene-wise genetic association analysis, a GSK3b-centric gene expression network had significant genetic associations, at a gene and network level, with risk for alcohol dependence in humans. These mutually reinforcing cross-species findings implicate GSK3B in neurobiological mechanisms controlling ethanol consumption, and as both a potential risk factor and therapeutic target for alcohol dependence.

Background: Parental alcohol problems are associated with adverse adolescent outcomes such as risky drinking and conduct problems. Important questions remain about the unique roles of fathers' and mothers' alcohol problems and differences and/or similarities in pathways of risk across ethnicity and gender. In this study, we used a family systems approach to consider spillover and crossover effects of fathers' and mothers' alcohol problems (number of alcohol dependence symptoms [ADS]) and parenting behaviors in relation to adolescents' risky drinking and conduct problems., Methods: The sample included 1,282 adolescents (aged 12 to 17) and their parents from the Collaborative Study on the Genetics of Alcoholism. Parents completed the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), and adolescents completed an adolescent version of SSAGA. Data were analyzed using multivariate structural equation modeling., Results: Fathers' ADS count was associated with higher adolescent risky drinking and conduct problems indirectly via disruption to fathers' and mothers' positive parenting behaviors, whereas mothers' ADS count was not associated with adolescents' risky drinking and conduct problems directly or indirectly via positive parenting behaviors. No differences in these associations were found across ethnic background and offspring gender., Conclusions: Findings highlight the importance of considering the unique roles of fathers' and mothers' ADS in influencing family processes and adolescent outcomes., (© 2018 by the Research Society on Alcoholism.)

Background: Despite consistent evidence of the heritability of alcohol use disorders (AUDs), few specific genes with an etiological role have been identified. It is likely that AUDs are highly polygenic; however, the etiological pathways and genetic variants involved may differ between populations. The aim of this study was thus to evaluate whether aggregate genetic risk for AUDs differed between clinically ascertained and population-based epidemiological samples., Methods: Four independent samples were obtained: 2 from unselected birth cohorts (Avon Longitudinal Study of Parents and Children [ALSPAC], N = 4,304; FinnTwin12 [FT12], N = 1,135) and 2 from families densely affected with AUDs, identified from treatment-seeking patients (Collaborative Study on the Genetics of Alcoholism, N = 2,097; Irish Affected Sib Pair Study of Alcohol Dependence, N = 706). AUD symptoms were assessed with clinical interviews, and participants of European ancestry were genotyped. Genomewide association was conducted separately in each sample, and the resulting association weights were used to create polygenic risk scores in each of the other samples (12 total discovery-validation pairs), and from meta-analyses within sample type. We then tested how well these aggregate genetic scores predicted AUD outcomes within and across sample types., Results: Polygenic scores derived from 1 population-based sample (ALSPAC) significantly predicted AUD symptoms in another population-based sample (FT12), but not in either clinically ascertained sample. Trend-level associations (uncorrected p < 0.05) were found for polygenic score predictions within sample types but no or negative predictions across sample types. Polygenic scores accounted for 0 to 1% of the variance in AUD symptoms., Conclusions: Though preliminary, these results provide suggestive evidence of differences in the genetic etiology of AUDs based on sample characteristics such as treatment-seeking status, which may index other important clinical or demographic factors that moderate genetic influences. Although the variance accounted for by genomewide polygenic scores remains low, future studies could improve gene identification efforts by amassing very large samples, or reducing genetic heterogeneity by informing analyses with other phenotypic information such as sample characteristics. Multiple complementary approaches may be needed to make progress in gene identification for this complex disorder., (Copyright © 2018 by the Research Society on Alcoholism.)

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., (Copyright © 2017 by the Research Society on Alcoholism.)

Background: Testing for direct gene or single nucleotide polymorphism replication of association across studies may not capture the true importance of a candidate locus; rather, we suggest that relevant replication across studies may be found at the level of a biological process. We previously observed that variation in 2 members of the switching defective/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex is associated with alcohol dependence (AD) in the Irish Affected Sib Pair Study for Alcohol Dependence. Here, we tested for association with alcohol-related outcomes using a set of genes functioning in the SWI/SNF complex in 2 independent samples., Methods: We used a set-based analysis to examine the 29 genes of the SWI/SNF complex for evidence of association with (i) AD in the adult Collaborative Study on the Genetics of Alcoholism (COGA) case-control sample and (ii) antisocial behavior, hypothesized to be a genetically related developmental precursor, in a younger population sample (Spit for Science [S4S])., Results: We found evidence for association of the SWI/SNF complex with AD in COGA (p = 0.0435) and more general antisocial behavior in S4S (p = 0.00026). The genes that contributed most strongly to the signal in COGA were SS18L1, SMARCD1, BRD7, BCL7B, SMARCB1, and BCL11A. In the S4S sample, ACTB, ARID2, BCL11A, BCL11B, BCL7B, BCL7C, DPF2, and DPF3 all contributed strongly to the signal., Conclusions: We detected associations between the SWI/SNF complex and AD in an adult population selected from treatment-seeking probands and antisocial behavior in an adolescent population sample. This provides strong support for a role for SWI/SNF in the development of alcohol-related problems., (Copyright © 2017 by the Research Society on Alcoholism.)

Twin studies indicate that latent genetic factors overlap across comorbid psychiatric disorders. In this study, we used a novel approach to elucidate shared genetic factors across psychiatric outcomes by clustering single nucleotide polymorphisms based on their genome-wide association patterns. We applied latent profile analysis (LPA) to p-values resulting from genome-wide association studies across three phenotypes: symptom counts of alcohol dependence (AD), antisocial personality disorder (ASP), and major depression (MD), using the European-American case-control genome-wide association study subsample of the collaborative study on the genetics of alcoholism (N = 1399). In the 3-class model, classes were characterized by overall low associations (85.6% of SNPs), relatively stronger association only with MD (6.8%), and stronger associations with AD and ASP but not with MD (7.6%), respectively. These results parallel the genetic factor structure identified in twin studies. The findings suggest that applying LPA to association results across multiple disorders may be a promising approach to identify the specific genetic etiologies underlying shared genetic variance.

Background: Alcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified., Methods: We conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)-response behaviors. We tested 1 primate-specific gene for expression differences in case/control postmortem brain tissue., Results: We detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C. elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C. elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc)., Conclusions: We detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders., (Copyright © 2017 by the Research Society on Alcoholism.)

Background: Alcohol use typically begins during adolescence and escalates into young adulthood. This represents an important period for the establishment of alcohol use and misuse patterns, which can have psychosocial and medical consequences. Although changes in alcohol use during this time have been phenotypically characterized, their genetic nature is poorly understood., Methods: Participants of the Avon Longitudinal Study of Parents and Children completed the Alcohol Use Disorders Identification Test (AUDIT) 4 times from age 16 to 20. We used Mplus to construct a growth model characterizing changes in AUDIT scores across time (N = 4,545, where data were available for at least 2 time points). The slope of the model was used as the phenotype in a genomewide association study (N = 3,380), followed by secondary genetic analyses., Results: No individual marker met genomewide significance criteria. Top markers mapped to biologically plausible candidate genes. The slope term was moderately heritable (h 2 SNP = 0.26, p = 0.009), and replication attempts using a meta-analysis of independent samples provided support for implicated variants at the aggregate level. Nominally significant (p < 0.00001) markers mapped to putatively active genomic regions in brain tissue more frequently than expected by chance., Conclusions: These results build on prior studies by demonstrating that common genetic variation impacts alcohol misuse trajectories. Influential loci map to genes that merit additional research, as well as to intergenic regions with regulatory functions in the central nervous system. These findings underscore the complex biological nature of alcohol misuse across development., (Copyright © 2016 by the Research Society on Alcoholism.)

The consequences of heavy alcohol use remain a serious public health problem. Consistent evidence has demonstrated that both genetic and social influences contribute to alcohol use. Research on gene-environment interaction (GxE) has also demonstrated that these social and genetic influences do not act independently. Instead, certain environmental contexts may limit or exacerbate an underlying genetic predisposition. However, much of the work on GxE and alcohol use has focused on adolescence and less is known about the important environmental contexts in young adulthood. Using data from the young adult wave of the Finnish Twin Study, FinnTwin12 (N = 3402), we used biometric twin modeling to test whether education moderated genetic risk for alcohol use as assessed by drinking frequency and intoxication frequency. Education is important because it offers greater access to personal resources and helps determine one's position in the broader stratification system. Results from the twin models show that education did not moderate genetic variance components and that genetic risk was constant across levels of education. Instead, education moderated environmental variance so that under conditions of low education, environmental influences explained more of the variation in alcohol use outcomes. The implications and limitations of these results are discussed., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Genetic and environmental factors influence substance use behaviors in youth. One of the known environmental risk factors is exposure to life stressors. The aim of this project is to study the interaction between NR3C1 and CRHBP, genes thought to be involved in stress pathways, exposure to stressful life events, and adolescent alcohol use/misuse., Methods: The sample included 541 African American individuals (ages 13-18) from the Genes, Environment, and Neighborhood Initiative, a subset of the Mobile Youth Survey sample from whom DNA and more extensive phenotypic data were collected. Participants were selected from high-poverty neighborhoods in Mobile, Alabama, with potential exposure to a variety of extreme life stressors., Results: A measure of stressful life events was significantly predictive of alcohol use/misuse. In addition, this association was significantly dependent upon the number of putative risk variants at rs1715749, a single-nucleotide polymorphism (SNP) in CRHBP (P ≤ .006). There was no significant interaction between NR3C1 and stressful life events with respect to alcohol use/misuse, after taking into account multiple testing., Conclusions: These findings suggest that CRHBP variants are potentially relevant for adolescent alcohol use/misuse among African American youth populations being reared within the context of stressful life events and warrant replication.

Objective: Variations in the genes encoding alcohol dehydrogenase (ADH) enzymes are associated with both alcohol consumption and dependence in multiple populations. Additionally, some environmental factors have been recognized as modifiers of these relationships. This study examined the modifying effect of religious involvement on relationships between ADH gene variants and alcohol consumption-related phenotypes., Method: Subjects were African American, European American, and Hispanic American adults with lifetime exposure to alcohol (N = 7,716; 53% female) from the Collaborative Study on the Genetics of Alcoholism. Genetic markers included ADH1Brs1229984, ADH1B-rs2066702, ADH1C-rs698, ADH4-rs1042364, and ADH4-rs1800759. Phenotypes were maximum drinks consumed in a 24-hour period and total number of alcohol dependence symptoms according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Religious involvement was defined by self-reported religious services attendance., Results: Both religious involvement and ADH1B-rs1229984 were negatively associated with the number of maximum drinks consumed and the number of lifetime alcohol dependence symptoms endorsed. The interactions of religious involvement with ADH1B-rs2066702, ADH1C-rs698, and ADH4-rs1042364 were significantly associated with maximum drinks and alcohol dependence symptoms. Risk variants had weaker associations with maximum drinks and alcohol dependence symptoms as a function of increasing religious involvement., Conclusions: This study provided initial evidence of a modifying effect for religious involvement on relationships between ADH variants and maximum drinks and alcohol dependence symptoms.

Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and upregulated in AD. Gene set enrichment analysis demonstrated that neuronal specific modules were enriched for genes involved in oxidative phosphorylation, mitochondrial dysfunction and MAPK signaling. Glial-specific modules were predominantly enriched for genes involved in processes related to immune functions, i.e. cytokine signaling (all adj. p≤ 0.05). In mRNA and miRNA modules, 461 and 25 candidate hub genes were identified, respectively. In contrast to the expected biological functions of miRNAs, correlation analyses between mRNA and miRNA hub genes revealed a higher number of positive than negative correlations (χ2 test p≤ 0.0001). Integration of hub gene expression with genome-wide genotypic data resulted in 591 mRNA cis-eQTLs and 62 miRNA cis-eQTLs. mRNA cis-eQTLs were significantly enriched for AD diagnosis and AD symptom counts (adj. p = 0.014 and p = 0.024, respectively) in AD GWAS signals in a large, independent genetic sample from the Collaborative Study on Genetics of Alcohol (COGA). In conclusion, our study identified putative gene network hubs coordinating mRNA and miRNA co-expression changes in the NAc of AD subjects, and our genetic (cis-eQTL) analysis provides novel insights into the etiological mechanisms of AD.

Objective: The genetic component of alcohol use disorder is substantial, but monozygotic twin discordance indicates a role for nonheritable differences that could be mediated by epigenetics. Despite growing evidence associating epigenetics and psychiatric disorders, it is unclear how epigenetics, particularly DNA methylation, relate to brain function and behavior, including drinking behavior., Method: The authors carried out a genome-wide analysis of DNA methylation of 18 monozygotic twin pairs discordant for alcohol use disorder and validated differentially methylated regions. After validation, the authors characterized these differentially methylated regions using personality trait assessment and functional MRI in a sample of 499 adolescents., Results: Hypermethylation in the 3'-protein-phosphatase-1G (PPM1G) gene locus was associated with alcohol use disorder. The authors found association of PPM1G hypermethylation with early escalation of alcohol use and increased impulsiveness. They also observed association of PPM1G hypermethylation with increased blood-oxygen-level-dependent response in the right subthalamic nucleus during an impulsiveness task., Conclusions: Overall, the authors provide first evidence for an epigenetic marker associated with alcohol consumption and its underlying neurobehavioral phenotype.

Objective: The gene GRM8, a metabotropic glutamate receptor, has emerged as a gene of interest for its possible role in the development of alcohol dependence, with evidence of association with an electrophysiological endophenotype and level of response to alcohol as well as suggestive evidence of association with alcohol dependence., Method: The present study further investigated the association between GRM8 and alcohol dependence symptom counts among young adults using a new sample of individuals collected as part of the prospective sample (ages 18-26 years; N = 842) from the Collaborative Study on the Genetics of Alcoholism (COGA)., Results: Two single-nucleotide polymorphisms were significantly associated with alcohol dependence in European Americans using the Nyholt corrected p value of .007: rs886003 (β = -.212, p = .0002) and rs17862325 (β = -.234, p < .0001), but not in African Americans, likely because of the lower power to detect association in this group., Conclusions: These results further implicate the role of glutamate receptor genes such as GRM8 in the development of alcohol dependence.

Aims: Alcohol problems (AP) contribute substantially to the global disease burden. Twin and family studies suggest that AP are genetically influenced, although few studies have identified variants or genes that are robustly associated with risk. This study identifies genetic and genomic influences on AP during young adulthood, which is often when drinking habits are established., Design: We conducted a genome-wide association study of AP. We further conducted gene-based tests, gene ontology analyses and functional genomic enrichment analyses to assess genomic factors beyond single variants that are relevant to AP., Setting: The Avon Longitudinal Study of Parents and Children, a large population-based study of a UK birth cohort., Participants: Genetic and phenotypical data were available for 4304 participants., Measurements: The AP phenotype was a factor score derived from items from the Alcohol Use Disorders Identification Test, symptoms of DSM-IV alcohol dependence, and three additional problem-related items., Findings: One variant met genome-wide significance criteria. Four out of 22,880 genes subjected to gene-based analyses survived a stringent significance threshold (q < 0.05); none of these have been implicated previously in alcohol-related phenotypes. Several biologically plausible gene ontologies were statistically over-represented among implicated single nucleotide polymorphisms (SNPs). SNPs on the Illumina 550 K SNP chip accounted for ~5% of the phenotypical variance in AP., Conclusions: Genetic and genomic factors appear to play a role in alcohol problems in young adults. Genes involved in nervous system-related processes, such as signal transduction and neurogenesis, potentially contribute to liability to alcohol problems, as do genes expressed in non-brain tissues., (© 2014 Society for the Study of Addiction.)

Objective: The purpose of this study was to evaluate evidence for association with a panel of genes previously associated with alcohol-related traits in a new sample of adolescent and young adult individuals (N = 2,128; 51% female) collected as part of the Collaborative Study on the Genetics of Alcoholism (COGA). We tested for association with phenotypes related to externalizing behavior, including diagnostic symptom counts for disorders on the externalizing spectrum (alcohol dependence, conduct disorder, adult antisocial personality disorder, and illicit drug dependence), and related behavioral/personality traits (Achenbach Externalizing, NEO Extraversion, NEO Conscientiousness, Zuckerman's Sensation Seeking, and the Barratt Impulsivity Scale) based on the substantial literature suggesting that these behaviors may be alternate manifestations of a shared genetic liability., Method: We tested for overall enrichment of the set of 215 genotyped single-nucleotide polymorphisms (SNPs) for each of the phenotypes. We conducted secondary analyses comparing results for sensation seeking with results for the other phenotypes., Results: For all phenotypes, there was significant enrichment of association results (p < .05) compared with chance expectations. The greatest number of significant results was observed with the phenotype Sensation Seeking. Secondary analyses indicated that the number of SNPs yielding p < .05 with Sensation Seeking was significantly greater than that observed for each of the other phenotypes., Conclusions: We find evidence for enrichment of association results across a spectrum of externalizing phenotypes with a panel of candidate genes/SNPs selected based on previous suggestion of association with alcohol-related outcomes. In particular, we find significant enrichment of effects with sensation seeking, suggesting that this may be a particularly salient behavior associated with risk for alcohol-related problems.

Family-based and genome-wide association studies (GWAS) of alcohol dependence (AD) have reported numerous associated variants. The clinical validity of these variants for predicting AD compared with family history information has not been reported. Using the Collaborative Study on the Genetics of Alcoholism (COGA) and the Study of Addiction: Genes and Environment (SAGE) GWAS samples, we examined the aggregate impact of multiple single nucleotide polymorphisms (SNPs) on risk prediction. We created genetic sum scores by adding risk alleles associated in discovery samples, and then tested the scores for their ability to discriminate between cases and controls in validation samples. Genetic sum scores were assessed separately for SNPs associated with AD in candidate gene studies and SNPs from GWAS analyses that met varying P-value thresholds. Candidate gene sum scores did not exhibit significant predictive accuracy. Family history was a better classifier of case-control status, with a significant area under the receiver operating characteristic curve (AUC) of 0.686 in COGA and 0.614 in SAGE. SNPs that met less stringent P-value thresholds of 0.01-0.50 in GWAS analyses yielded significant AUC estimates, ranging from mean estimates of 0.549 for SNPs with P < 0.01 to 0.565 for SNPs with P < 0.50. This study suggests that SNPs currently have limited clinical utility, but there is potential for enhanced predictive ability with better understanding of the large number of variants that might contribute to risk., (© 2013 The Authors, Addiction Biology © 2013 Society for the Study of Addiction.)

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., (Copyright © 2013 by the Research Society on Alcoholism.)

Objective: Depression and alcohol dependence (AD) are common psychiatric disorders that often co-occur. Both disorders are genetically influenced, with heritability estimates in the range of 35-60%. In addition, evidence from twin studies suggests that AD and depression are genetically correlated. Herein, we report results from a genome-wide association study of a comorbid phenotype, in which cases meet the Diagnostic and Statistical Manual of Mental Disorders-IV symptom threshold for major depressive symptomatology and the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for AD., Methods: Samples (N=467 cases and N=407 controls) were of European-American descent and were genotyped using the Illumina Human 1M BeadChip array., Results: Although no single-nucleotide polymorphism (SNP) meets genome-wide significance criteria, we identified 10 markers with P values less than 1 × 10(-5), seven of which are located in known genes, which have not been previously implicated in either disorder. Genes harboring SNPs yielding P values less than 1 × 10(-5) are functionally enriched for a number of gene ontology categories, notably several related to glutamatergic function. Investigation of expression localization using online resources suggests that these genes are expressed across a variety of tissues, including behaviorally relevant brain regions. Genes that have been previously associated with depression, AD, or other addiction-related phenotypes - such as CDH13, CSMD2, GRID1, and HTR1B - were implicated by nominally significant SNPs. Finally, the degree of overlap of significant SNPs between a comorbid phenotype and an AD-only phenotype is modest., Conclusion: These results underscore the complex genomic influences on psychiatric phenotypes and suggest that a comorbid phenotype is partially influenced by genetic variants that do not affect AD alone.

Background: A variety of species and experimental designs have been used to study genetic influences on alcohol dependence, ethanol response, and related traits. Integration of these heterogeneous data can be used to produce a ranked target gene list for additional investigation., Results: In this study, we performed a unique multi-species evidence-based data integration using three microarray experiments in mice or humans that generated an initial alcohol dependence (AD) related genes list, human linkage and association results, and gene sets implicated in C. elegans and Drosophila. We then used permutation and false discovery rate (FDR) analyses on the genome-wide association studies (GWAS) dataset from the Collaborative Study on the Genetics of Alcoholism (COGA) to evaluate the ranking results and weighting matrices. We found one weighting score matrix could increase FDR based q-values for a list of 47 genes with a score greater than 2. Our follow up functional enrichment tests revealed these genes were primarily involved in brain responses to ethanol and neural adaptations occurring with alcoholism., Conclusions: These results, along with our experimental validation of specific genes in mice, C. elegans and Drosophila, suggest that a cross-species evidence-based approach is useful to identify candidate genes contributing to alcoholism.

Conduct disorder (CD) is one of the most prevalent childhood psychiatric conditions, and is associated with a number of serious concomitant and future problems. CD symptomatology is known to have a considerable genetic component, with heritability estimates in the range of 50%. Despite this, there is a relative paucity of studies aimed at identifying genes involved in the susceptibility to CD. In this study, we report results from a genome-wide association study of CD symptoms. CD symptoms were retrospectively reported by a psychiatric interview among a sample of cases and controls, in which cases met the criteria for alcohol dependence. Our primary phenotype was the natural log transformation of the number of CD symptoms that were endorsed, with data available for 3963 individuals who were genotyped on the Illumina Human 1M beadchip array. Secondary analyses are presented for case versus control status, in which caseness was established as endorsing three or more CD symptoms (N = 872 with CD and N = 3091 without CD). We find four markers that meet the criteria for genome-wide significance (P<5 × 10(-8)) with the CD symptom count, two of which are located in the gene C1QTNF7 (C1q and tumor necrosis factor-related protein 7). There were six additional SNPs in the gene that yielded converging evidence of association. These data provide the first evidence of a specific gene that is associated with CD symptomatology. None of the top signals resided in traditional candidate genes, underscoring the importance of a genome-wide approach for identifying novel variants involved in this serious childhood disorder.

Background: While genetic influences on alcohol dependence (AD) are substantial, progress in the identification of individual genetic variants that impact on risk has been difficult., Methods: We performed a genome-wide association study on 3,169 alcohol consuming subjects from the population-based Molecular Genetics of Schizophrenia (MGS2) control sample. Subjects were asked 7 questions about symptoms of AD which were analyzed by confirmatory factor analysis. Genotyping was performed using the Affymetrix 6.0 array. Three sets of analyses were conducted separately for European American (EA, n = 2,357) and African-American (AA, n = 812) subjects: individual single nucleotide polymorphisms (SNPs), candidate genes and enriched pathways using gene ontology (GO) categories., Results: The symptoms of AD formed a highly coherent single factor. No SNP approached genome-wide significance. In the EA sample, the most significant intragenic SNP was in KCNMA1, the human homolog of the slo-1 gene in C. Elegans. Genes with clusters of significant SNPs included AKAP9, phosphatidylinositol glycan anchor biosynthesis, class G (PIGG), and KCNMA1. In the AA sample, the most significant intragenic SNP was CEACAM6 and genes showing empirically significant SNPs included KCNQ5, SLC35B4, and MGLL. In the candidate gene based analyses, the most significant findings were with ADH1C, nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1) and ankyrin repeat and kinase domain containing 1 (ANKK1) in the EA sample, and ADH5, POMC, and CHRM2 in the AA sample. The ALIGATOR program identified a significant excess of associated SNPs within and near genes in a substantial number of GO categories over a range of statistical stringencies in both the EA and AA sample., Conclusions: While we cannot be highly confident about any single result from these analyses, a number of findings were suggestive and worthy of follow-up. Although quite large samples will be needed to obtain requisite power, the study of AD symptoms in general population samples is a viable complement to case-control studies in identifying genetic risk variants for AD., (Copyright © 2011 by the Research Society on Alcoholism.)

Background: The Rutgers Alcohol Problem Index (RAPI) is widely used to assess adolescent drinking-related problems. We asked how well RAPI, administered in late adolescence, predicts alcohol diagnoses at age 25 in a 7-year follow-up., Methods: At age 18, a population-based sample of Finnish twins completed RAPI by postal questionnaire; 597 (300 male) twins, from pairs discordant and concordant for age 18 RAPI scores, were interviewed at age 25 with the SSAGA, yielding DSM-IIIR diagnoses. Polychoric correlations between RAPI and alcohol diagnoses and symptoms, the area under the response operator characteristic (ROC) curve, and the odds ratio of outcome diagnosis per unit change in adolescent RAPI were analyzed. Twin pairs discordant for both adolescent RAPI and adult diagnoses permitted within-family replications for the full sample and separately by sex., Results: Nearly half the interviewed twins met diagnostic criteria for alcohol dependency (46.2%) or abuse (1.5%). Age 18 RAPI scores significantly correlated with diagnoses (0.52) and symptom counts (0.55). ROC analysis found a 74% probability that adolescent RAPI scores will be higher among those with an alcohol diagnosis at age 25 than for those without. The odds ratio of outcome alcohol diagnosis per unit increase in adolescent 18 RAPI exceeded 10.0. Within-family comparisons of 117 twin pairs discordant for both age 18 RAPI and age 25 alcohol diagnoses replicated the between-family associations. In both between-family and within-family analyses, RAPI was more predictive of alcohol diagnoses among females., Conclusions: Our results offer evidence, including that from informative comparisons of co-twins discordant for both predictor and outcome, that RAPI scores in late adolescence robustly predict alcohol diagnoses in early adulthood. Accordingly, our results also provide new evidence that one pathway to problem drinking in early adulthood is a direct one from problem drinking in adolescence., (Copyright © 2011 by the Research Society on Alcoholism.)

Background: Over 50 years of evidence from research has established that the central dopaminergic reward pathway is likely involved in alcohol dependence (AD). Additional evidence supports a role for dopamine (DA) in other disinhibitory psychopathology, which is often comorbid with AD. Family and twin studies demonstrate that a common genetic component accounts for most of the genetic variance in these traits. Thus, DA-related genes represent putative candidates for the genetic risk that underlies not only AD but also behavioral disinhibition. Many linkage and association studies have examined these relationships with inconsistent results, possibly because of low power, poor marker coverage, and/or an inappropriate correction for multiple testing., Methods: We conducted an association study on the products encoded by 10 DA-related genes (DRD1-D5, SLC18A2, SLC6A3, DDC, TH, COMT) using a large, ethnically homogeneous sample with severe AD (n = 545) and screened controls (n = 509). We collected genotypes from linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) and employed a gene-based method of correction. We tested for association with AD diagnosis in cases and controls and with a variety of alcohol-related traits (including age-at-onset, initial sensitivity, tolerance, maximum daily drinks, and a withdrawal factor score), disinhibitory symptoms, and a disinhibitory factor score in cases only. A total of 135 SNPs were genotyped using the Illumina GoldenGate and Taqman Assays-on-Demand protocols., Results: Of the 101 SNPs entered into standard analysis, 6 independent SNPs from 5 DA genes were associated with AD or a quantitative alcohol-related trait. Two SNPs across 2 genes were associated with a disinhibitory symptom count, while 1 SNP in DRD5 was positive for association with the general disinhibitory factor score., Conclusions: Our study provides evidence of modest associations between a small number of DA-related genes and AD as well as a range of alcohol-related traits and measures of behavioral disinhibition. While we did conduct gene-based correction for multiple testing, we did not correct for multiple traits because the traits are correlated. However, false-positive findings remain possible, so our results must be interpreted with caution., (Copyright © 2010 by the Research Society on Alcoholism. No claim to original U.S. government works.)

Twin studies provide strong evidence that there is a shared genetic liability that predisposes to a number of different psychiatric outcomes related to behavioral disinhibition. Further, alcohol dependence comorbid with other disinhibitory disorders is particularly heritable. Chromosome 2p14-2q14.3 has been linked to multiple psychiatric conditions related to behavioral undercontrol. In the Collaborative Study on the Genetics of Alcoholism (COGA), we previously reported linkage to this region with alcohol dependence (AD), suicide attempts (SUI), and conduct disorder (CD). In this study, we follow-up on these previous reports of linkage by combining the phenotypes in analyses that jointly consider the presence of multiple conditions. Linkage analyses of the combined phenotype of AD with CD or SUI results in a maximum LOD score of 5.4 in this region. In addition to this primary linkage peak, independent samples have reported linkage to other alcohol-related phenotypes across chromosome 2. Accordingly, we followed-up these linkage signals by testing for association with SNPs across chromosome 2 in a case-control sample, in which a subset of the cases consisted of alcohol-dependent probands from the linkage sample. We find evidence of association with the combined AD with CD or SUI phenotype, with 23 genes surviving permutation testing. The number of associated genes across the chromosome may explain the persistent linkage findings reported on chromosome 2 across a number of independent studies of alcohol and disinhibitory phenotypes. Further, none of the genes were located directly under the primary COGA linkage peak, which has implications for association tests following-up linkage peaks., ((c) 2010 Wiley-Liss, Inc.)

Studies of alcohol dependence (AD) have consistently found evidence of linkage on chromosome 4q21-q32. A genome-wide linkage scan in the Irish Affected Sib Pair Study of Alcohol Dependence (IASPSAD) sample also provided its strongest evidence of linkage on chromosome 4q22-q32 using an index of AD severity based on the count of DSM-IV AD symptoms (ADSX; LOD = 4.59). We conducted a systematic, gene-centric association study using 518 LD-tagging single nucleotide polymorphisms (SNPs) in the 65 known and predicted genes within the 1-LOD interval surrounding the linkage peak. Case-only regression analysis with the quantitative variable of ADSX was performed in the 562 genetically independent cases; nominal support for association was demonstrated by 32 tagging SNPs in 14 genes. We did not observe study-wide significance, but gene-wise correction for multiple testing with the Nyholt procedure yielded empirical evidence of association with two genes, DKK2 (dickkopf homolog 2) (P = 0.007) and EGF (epidermal growth factor) (P = 0.025) in the IASPSAD sample. Three SNPs in DKK2 (rs427983; rs419558; rs399087) demonstrated empirical significance. Assessment of possible replication in 847 cases of European descent from a large independent sample, the Collaborative Study of the Genetics of Alcoholism, yielded replication for DKK2 but not EGF. We observed genotypic and phenotypic replication for DKK2 with the three SNPs yielding significant association with ADSX in the IASPSAD sample. Haplotype-specific expression measurements in post-mortem tissue samples suggested a functional role for DKK2. This evidence notwithstanding, replication is needed before confidence can be placed in these findings.

Background: Alcohol dependence is a complex disease, and although linkage and candidate gene studies have identified several genes associated with the risk for alcoholism, these explain only a portion of the risk., Methods: We carried out a genome-wide association study (GWAS) on a case-control sample drawn from the families in the Collaborative Study on the Genetics of Alcoholism. The cases all met diagnostic criteria for alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition; controls all consumed alcohol but were not dependent on alcohol or illicit drugs. To prioritize among the strongest candidates, we genotyped most of the top 199 single nucleotide polymorphisms (SNPs) (p < or = 2.1 x 10(-4)) in a sample of alcohol-dependent families and performed pedigree-based association analysis. We also examined whether the genes harboring the top SNPs were expressed in human brain or were differentially expressed in the presence of ethanol in lymphoblastoid cells., Results: Although no single SNP met genome-wide criteria for significance, there were several clusters of SNPs that provided mutual support. Combining evidence from the case-control study, the follow-up in families, and gene expression provided strongest support for the association of a cluster of genes on chromosome 11 (SLC22A18, PHLDA2, NAP1L4, SNORA54, CARS, and OSBPL5) with alcohol dependence. Several SNPs nominated as candidates in earlier GWAS studies replicated in ours, including CPE, DNASE2B, SLC10A2, ARL6IP5, ID4, GATA4, SYNE1, and ADCY3., Conclusions: We have identified several promising associations that warrant further examination in independent samples.

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.

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.