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Alcohol use is influenced by genetic and environmental factors. We examined the interactive effects between genome-wide polygenic risk scores for alcohol use (alc-PRS) and social support in relation to alcohol use among European American (EA) and African American (AA) adults across sex and developmental stages (emerging adulthood, young adulthood, and middle adulthood). Data were drawn from 4,011 EA and 1,274 AA adults from the Collaborative Study on the Genetics of Alcoholism who were between ages 18-65 and had ever used alcohol. Participants completed the Semi-Structured Assessment for the Genetics of Alcoholism and provided saliva or blood samples for genotyping. Results indicated that social support from friends, but not family, moderated the association between alc-PRS and alcohol use among EAs and AAs (only in middle adulthood for AAs); alc-PRS was associated with higher levels of alcohol use when friend support was low, but not when friend support was high. Associations were similar across sex but differed across developmental stages. Findings support the important role of social support from friends in buffering genetic risk for alcohol use among EA and AA adults and highlight the need to consider developmental changes in the role of social support in relation to alcohol use.

ImportanceCurrent Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) diagnoses of substance use disorders rely on criterion count-based approaches, disregarding severity grading indexed by individual criteria.ObjectiveTo examine correlates of alcohol use disorder (AUD) across count-based severity groups (ie, mild, moderate, mild-to-moderate, severe), identify specific diagnostic criteria indicative of greater severity, and evaluate whether specific criteria within mild-to-moderate AUD differentiate across relevant correlates and manifest in greater hazards of severe AUD development.Design, setting, and participantsThis cohort study involved 2 cohorts from the family-based Collaborative Study on the Genetics of Alcoholism (COGA) with 7 sites across the United States: cross-sectional (assessed 1991-2005) and longitudinal (assessed 2004-2019). Statistical analyses were conducted from December 2022 to June 2023.Main outcomes and measuresSociodemographic, alcohol-related, psychiatric comorbidity, brain electroencephalography (EEG), and AUD polygenic score measures as correlates of DSM-5 AUD levels (ie, mild, moderate, severe) and criterion severity-defined mild-to-moderate AUD diagnostic groups (ie, low-risk vs high-risk mild-to-moderate).ResultsA total of 13 110 individuals from the cross-sectional COGA cohort (mean [SD] age, 37.8 [14.2] years) and 2818 individuals from the longitudinal COGA cohort (mean baseline [SD] age, 16.1 [3.2] years) were included. Associations with alcohol-related, psychiatric, EEG, and AUD polygenic score measures reinforced the role of increasing criterion counts as indexing severity. Yet within mild-to-moderate AUD (2-5 criteria), the presence of specific high-risk criteria (eg, withdrawal) identified a group reporting heavier drinking and greater psychiatric comorbidity even after accounting for criterion count differences. In longitudinal analyses, prior mild-to-moderate AUD characterized by endorsement of at least 1 high-risk criterion was associated with more accelerated progression to severe AUD (adjusted hazard ratio [aHR], 11.62; 95% CI, 7.54-17.92) compared with prior mild-to-moderate AUD without endorsement of high-risk criteria (aHR, 5.64; 95% CI, 3.28-9.70), independent of criterion count.Conclusions and relevanceIn this cohort study of a combined 15 928 individuals, findings suggested that simple count-based AUD diagnostic approaches to estimating severe AUD vulnerability, which ignore heterogeneity among criteria, may be improved by emphasizing specific high-risk criteria. Such emphasis may allow better focus on individuals at the greatest risk and improve understanding of the development of AUD.

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 (βindirect = -0.018 [-0.026, -0.011]) and intoxication (βindirect = -0.015 [-0.023, -0.008]), greater lifetime maximum drinks (βindirect = 0.006 [0.002, 0.01]) and more lifetime AUD criteria (βindirect = 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.

Memory problems are common among older adults with a history of alcohol use disorder (AUD). Employing a machine learning framework, the current study investigates the use of multi-domain features to classify individuals with and without alcohol-induced memory problems. A group of 94 individuals (ages 50-81 years) with alcohol-induced memory problems (the memory group) were compared with a matched control group who did not have memory problems. The random forests model identified specific features from each domain that contributed to the classification of the memory group vs. the control group (AUC = 88.29%). Specifically, individuals from the memory group manifested a predominant pattern of hyperconnectivity across the default mode network regions except for some connections involving the anterior cingulate cortex, which were predominantly hypoconnected. Other significant contributing features were: (i) polygenic risk scores for AUD, (ii) alcohol consumption and related health consequences during the past five years, such as health problems, past negative experiences, withdrawal symptoms, and the largest number of drinks in a day during the past twelve months, and (iii) elevated neuroticism and increased harm avoidance, and fewer positive "uplift" life events. At the neural systems level, hyperconnectivity across the default mode network regions, including the connections across the hippocampal hub regions, in individuals with memory problems may indicate dysregulation in neural information processing. Overall, the study outlines the importance of utilizing multidomain features, consisting of resting-state brain connectivity data collected ~18 years ago, together with personality, life experiences, polygenic risk, and alcohol consumption and related consequences, to predict the alcohol-related memory problems that arise in later life.

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury1-4. These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries5. Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.

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 (NEUR = 12,659) and African (NAFR = 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.

BackgroundGenome-wide association studies have been conducted in alcohol use disorder (AUD), and they permit the use of polygenic risk scores (PRSs), in combination with clinical variables, to predict the onset of AUD in vulnerable populations.MethodsA total of 2794 adolescent/young adult subjects from the Collaborative Study on the Genetics of Alcoholism were followed, with clinical assessments every 2 years. Subjects were genotyped using a genome-wide chip. Separate PRS analyses were performed for subjects of European ancestry and African ancestry. Age of onset of DSM-5 AUD was evaluated using the Cox proportional hazard model. Predictive power was assessed using receiver operating characteristic curves and by analysis of the distribution of PRS.ResultsEuropean ancestry subjects with higher than median PRSs were at greater risk for onset of AUD than subjects with lower than median PRSs (p = 3 × 10-7). Area under the curve for the receiver operating characteristic analysis peaked at 0.88 to 0.95 using PRS plus sex, family history, comorbid disorders, age at first drink, and peer drinking; predictive power was primarily driven by clinical variables. In this high-risk sample, European ancestry subjects with a PRS score in the highest quartile showed a 72% risk for developing AUD and a 35% risk of developing severe AUD (compared with risks of 54% and 16%, respectively, in the lowest quartile).ConclusionsPredictive power for PRSs in the extremes of the distribution suggests that these may have future clinical utility. Uncertainties in interpretation at the individual level still preclude current application.

ObjectiveTo examine associations between alcohol use disorder (AUD), its psychiatric comorbidities, and their interactions, with marital outcomes in a diverse high-risk, genetically informative sample.MethodParticipants 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, Mage ∼ 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.ResultsAmong EA participants, those with AUD and CAN were less likely to marry (hazard ratios [HRs] 0.70-0.83, ps < 0.01). Among AA participants, those with AUD and TOB were less likely to marry (HRs 0.66-0.82, ps < 0.05) and those with MDD were more likely to marry (HR = 1.34, ps < 0.01). Among EA participants, AUD, CAN, TOB, and MDD were associated with higher odds of divorce (odds ratios [ORs] 1.59-2.21, ps < 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.ConclusionsIn 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).

Genetic predispositions and environmental influences both play an important role in adolescent externalizing behavior; however, they are not always independent. To elucidate gene-environment interplay, we examined the interrelationships between externalizing polygenic risk scores, parental knowledge, and peer substance use in impacting adolescent externalizing behavior across two time-points in a high-risk longitudinal sample of 1,200 adolescents (764 European and 436 African ancestry; Mage = 12.99) from the Collaborative Study on the Genetics of Alcoholism. Results from multivariate path analysis indicated that externalizing polygenic scores were directly associated with adolescent externalizing behavior but also indirectly via peer substance use, in the European ancestry sample. No significant polygenic association nor indirect effects of genetic risk were observed in the African ancestry group, likely due to more limited power. Our findings underscore the importance of gene-environment interplay and suggest peer substance use may be a mechanism through which genetic risk influences adolescent externalizing behavior.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

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.

Handedness has been extensively studied because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and the International Handedness Consortium, we conducted a genome-wide association meta-analysis of handedness (N = 1,766,671). We found 41 loci associated (P

BackgroundSuicidal thoughts and behaviors (STBs) and nonsuicidal self-injury (NSSI) behaviors are moderately heritable and may reflect an underlying predisposition to depression, impulsivity, and cognitive vulnerabilities to varying degrees.ObjectivesWe aimed to estimate the degrees of association between genetic liability to depression, impulsivity, and cognitive performance and STBs and NSSI in a high-risk sample.MethodsWe used data on 7,482 individuals of European ancestry and 3,359 individuals of African ancestry from the Collaborative Study on the Genetics of Alcoholism to examine the links between polygenic scores (PGSs) for depression, impulsivity/risk-taking, and cognitive performance with 3 self-reported indices of STBs (suicidal ideation, persistent suicidal ideation defined as ideation occurring on at least 7 consecutive days, and suicide attempt) and with NSSI.ResultsThe PGS for depression was significantly associated with all 4 primary self-harm measures, explaining 0.6-2.5% of the variance. The PGS for risk-taking behaviors was also associated with all 4 self-harm behaviors in baseline models, but was no longer associated after controlling for a lifetime measure of DSM-IV alcohol dependence and abuse symptom counts. Polygenic predisposition for cognitive performance was negatively associated with suicide attempts (q = 3.8e-4) but was not significantly associated with suicidal ideation nor NSSI. We did not find any significant associations in the African ancestry subset, likely due to smaller sample sizes.ConclusionsOur results encourage the study of STB as transdiagnostic outcomes that show genetic overlap with a range of risk factors.

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 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

Genetic factors explain a major proportion of human height variation, but differences in mean stature have also been found between socio-economic categories suggesting a possible effect of environment. By utilizing a classical twin design which allows decomposing the variation of height into genetic and environmental components, we tested the hypothesis that environmental variation in height is greater in offspring of lower educated parents. Twin data from 29 cohorts including 65,978 complete twin pairs with information on height at ages 1 to 69 years and on parental education were pooled allowing the analyses at different ages and in three geographic-cultural regions (Europe, North America and Australia, and East Asia). Parental education mostly showed a positive association with offspring height, with significant associations in mid-childhood and from adolescence onwards. In variance decomposition modeling, the genetic and environmental variance components of height did not show a consistent relation to parental education. A random-effects meta-regression analysis of the aggregate-level data showed a trend towards greater shared environmental variation of height in low parental education families. In conclusion, in our very large dataset from twin cohorts around the globe, these results provide only weak evidence for the study hypothesis.

BackgroundGenomewide association studies (GWAS) have begun to identify loci related to alcohol consumption, but little is known about whether this genetic propensity overlaps with specific indices of problem drinking in ascertained samples.MethodsIn 6,731 European Americans who had been exposed to alcohol, we examined whether polygenic risk scores (PRS) from a GWAS of weekly alcohol consumption in the UK Biobank predicted variance in 6 alcohol-related phenotypes: alcohol use, maximum drinks within 24 hours (MAXD), total score on the Self-Rating of the Effects of Ethanol Questionnaire (SRE-T), DSM-IV alcohol dependence (DSM4AD), DSM-5 alcohol use disorder symptom counts (DSM5AUDSX), and reduction/cessation of problematic drinking. We also examined the extent to which an single nucleotide polymorphism (rs1229984) in ADH1B, which is strongly associated with both alcohol consumption and dependence, contributed to the polygenic association with these phenotypes and whether PRS interacted with sex, age, or family history of alcoholism to predict alcohol-related outcomes. We performed mixed-effect regression analyses, with family membership and recruitment site included as random effects, as well as survival modeling of age of onset of DSM4AD.ResultsPRS for alcohol consumption significantly predicted variance in 5 of the 6 outcomes: alcohol use (Δmarginal R2  = 1.39%, Δ area under the curve [AUC] = 0.011), DSM4AD (Δmarginal R2  = 0.56%; ΔAUC = 0.003), DSM5AUDSX (Δmarginal R2  = 0.49%), MAXD (Δmarginal R2  = 0.31%), and SRE-T (Δmarginal R2  = 0.22%). PRS were also associated with onset of DSM4AD (hazard ratio = 1.11, p = 2.08e-5). The inclusion of rs1229984 attenuated the effects of the alcohol consumption PRS, particularly for DSM4AD and DSM5AUDSX, but the PRS continued to exert an independent effect for all 5 alcohol measures (Δmarginal R2 after controlling for ADH1B = 0.14 to 1.22%). Interactions between PRS and sex, age, or family history were nonsignificant.ConclusionsGenetic propensity for typical alcohol consumption was associated with alcohol use and was also associated with 4 of the additional 5 outcomes, though the variance explained in this sample was modest. Future GWAS that focus on the multifaceted nature of AUD, which goes beyond consumption, might reveal additional information regarding the polygenic underpinnings of problem drinking.

Background and aimsFew studies have explored how polygenic propensity to cannabis use unfolds across development, and no studies have yet examined this question in the context of environmental contributions such as peer cannabis use. Outlining the factors that contribute to progression from cannabis initiation to problem use over time may ultimately provide insights into mechanisms for targeted interventions. We sought to examine the relationships between polygenic liability for cannabis use, cannabis use trajectories from ages 12-30 years and perceived peer cannabis use at ages 12-17 years.DesignMixed-effect logistic and linear regressions were used to examine associations between polygenic risk scores, cannabis use trajectory membership and perceived peer cannabis use.SettingUnited States.ParticipantsFrom the Collaborative Study on the Genetics of Alcoholism (COGA) study, a cohort of 1167 individuals aged 12-26 years at their baseline (i.e. first) interview.MeasurementsKey measurements included life-time cannabis use (yes/no), frequency of past 12-month cannabis use, maximum life-time frequency of cannabis use, cannabis use disorder (using DSM-5 criteria) and perceived peer cannabis use. Polygenic risk scores (PRS) were created using summary statistics from a large (n = 162 082) genome-wide association study (GWAS) of cannabis use.FindingsThree trajectories reflecting no/low (n = 844), moderate (n = 137) and high (n = 186) use were identified. PRS were significantly associated with trajectory membership [P = 0.002-0.006, maximum conditional R2  = 1.4%, odds ratios (ORs) = 1.40-1.49]. Individuals who reported that most/all of their best friends used cannabis had significantly higher PRS than those who reported that none of their friends were users [OR = 1.35, 95% confidence interval (CI) = 1.04, 1.75, P = 0.023]. Perceived peer use itself explained up to 11.3% of the variance in trajectory class membership (OR = 1.50-4.65). When peer cannabis use and the cannabis use PRS were entered into the model simultaneously, both the PRS and peer use continued to be significantly associated with class membership (P

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.

We study a nonparametric test procedure based on order statistics for testing the null hypothesis of equality of two continuous distributions. The exact null distribution of the proposed test statistic is obtained using an enumeration method and a novel combinatorial argument. A recurrence relation for the probability generating function and a sequential approach for computing the mean and variance of the distribution are given. Critical values and characteristics of the distribution for selected small sample sizes are presented. For the Lehmann alternative family, the exact power function of the new test is derived, and its power performance is examined. We also study the power performance of the proposed test under the location-shift and scale-shift alternatives using Monte Carlo simulations and observe its superior performance when compared to commonly used nonparametric tests under various scenarios. A generalization of the proposed procedure for unequal sample sizes is discussed. An illustrative example and some concluding remarks are provided. [ABSTRACT FROM AUTHOR]

ObjectiveVariations 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.MethodSubjects 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.ResultsBoth 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.ConclusionsThis study provided initial evidence of a modifying effect for religious involvement on relationships between ADH variants and maximum drinks and alcohol dependence symptoms.

In this project, we aimed to bring large-scale gene identification findings into a developmental psychopathology framework. Using a family-based sample, we tested whether polygenic scores for externalizing disorders-based on single nucleotide polymorphism weights derived from genome-wide association study results in adults (n = 1,249)-predicted externalizing disorders, subclinical externalizing behavior, and impulsivity-related traits adolescents (n = 248) and young adults (n = 207), and whether parenting and peer factors in adolescence moderated polygenic risk to predict externalizing disorders. Polygenic scores predicted externalizing disorders in adolescents and young adults, even after controlling for parental externalizing disorder history. Polygenic scores also predicted subclinical externalizing behavior and impulsivity traits in the adolescents and young adults. Adolescent parental monitoring and peer substance use moderated polygenic scores to predict externalizing disorders. This illustrates how state of the science genetics can be integrated with psychological science to identify how genetic risk contributes to the development of psychopathology.

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 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, Zuckermans 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.

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. [ABSTRACT FROM AUTHOR]

Background: In the United States, ~50% of individuals who meet criteria for alcohol use disorder (AUD) during their lifetimes do not remit. We previously reported that a polygenic score for AUD (PGSAUD) was positively associated with AUD severity as measured by DSM‐5 lifetime criterion count, and AUD severity was negatively associated with remission. Thus, we hypothesized that PGSAUD would be negatively associated with remission. Methods: Individuals of European (EA) and African ancestry (AA) from the Collaborative Study on the Genetics of Alcoholism (COGA) who met lifetime criteria for AUD, and two EA cohorts ascertained for studies of liver diseases and substance use disorders from the Indiana Biobank were included. In COGA, 12‐month remission was defined as any period of ≥12 consecutive months without meeting AUD criteria except craving and was further categorized as abstinent and non‐abstinent. In the Indiana Biobank, remission was defined based on ICD codes and could not be further distinguished as abstinent or non‐abstinent. Sex and age were included as covariates. COGA analyses included additional adjustment for AUD severity, family history of remission, and AUD treatment history. Results: In COGA EA, PGSAUD was negatively associated with 12‐month and non‐abstinent remission (p ≤ 0.013, βs between −0.15 and −0.10) after adjusting for all covariates. In contrast to the COGA findings, PGSAUD was positively associated with remission (p = 0.004, β = 0.28) in the Indiana Biobank liver diseases cohort but not in the Indiana Biobank substance use disorder cohort (p = 0.17, β = 0.15). Conclusions: PGSAUD was negatively associated with 12‐month and non‐abstinent remission in COGA EA, independent of behavioral measures of AUD severity and family history of remission. The discrepant results in COGA and the Indiana Biobank could reflect different ascertainment strategies: the Indiana Biobank participants were older and had higher rates of liver disease, suggesting that these individuals remitted due to alcohol‐related health conditions that manifested in later life. [ABSTRACT FROM AUTHOR]

The goals of the present study were to describe the development of the first national longitudinal study of collegiate recovery program (CRP) students; provide an updated characterization of CRP students' demographics, past problem severity, and current recovery-related functioning; and examine the perceived impact of COVID-19 on CRP students' recovery. Universities and community colleges with CRPs across the United States and Ontario, Canada, were invited to partner on this project. Launched in fall 2020, three cohorts of participants were recruited. All participants who completed the baseline survey (N = 334 from 43 CRPs) were invited to complete follow-up surveys. The sample was composed of mostly undergraduate, White, cisgender women averaging 29 years old at baseline. They reported challenging backgrounds, including high levels of polysubstance use, alcohol/substance problem severity, mental health challenges, and involvement with the criminal legal system. Despite such adversity, they evidenced high levels of recovery-related functioning. Recovery capital and quality of life were high. Students reported an average of nearly four years in recovery, with most having between two and four years of abstinence from their primary substance of choice. COVID-19 represented a substantial source of stress for many, impacting some students' abstinence and recovery-related functioning. Results generally parallel findings from the only other national study of CRP students conducted a decade ago, providing a much-needed update and novel insights into CRP students. Findings can inform our understanding of the CRP student population and can be used to tailor CRP design and service offerings to students' backgrounds and needs. [ABSTRACT FROM AUTHOR]

Abstract 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.