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BACKGROUND: Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk. METHODS: Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11-36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones. RESULTS: Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20). CONCLUSIONS: Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.

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.

Some sources report increases in alcohol use have been observed since the start of the COVID-19 pandemic, particularly among women. Cross-sectional studies suggest that specific COVID-19-related stressful experiences (e.g., social disconnection) may be driving such increases in the general population. Few studies have explored these topics among individuals with a history of Alcohol Use Disorders (AUD), an especially vulnerable population. Drawing on recent data collected by the Collaborative Study on the Genetics of Alcoholism (COGA; COVID-19 study N = 1651, 62% women, age range: 30-91) in conjunction with AUD history data collected on the sample since 1990, we investigated associations of COVID-19 related stressors and coping activities with changes in drunkenness frequency since the start of the pandemic. Analyses were conducted for those without a history of AUD (N: 645) and three groups of participants with a history of AUD prior to the start of the pandemic: (1) those experiencing AUD symptoms (N: 606), (2) those in remission who were drinking (N: 231), and (3) those in remission who were abstinent (had not consumed alcohol for 5+ years; N: 169). Gender-stratified models were also examined. Exploratory analyses examined the moderating effects of 'problematic alcohol use' polygenic risk scores (PRS) and neural connectivity (i.e., posterior interhemispheric alpha EEG coherence) on associations between COVID-19 stressors and coping activities with changes in the frequency of drunkenness. Increases in drunkenness frequency since the start of the pandemic were higher among those with a lifetime AUD diagnosis experiencing symptoms prior to the start of the pandemic (14% reported increased drunkenness) when compared to those without a history of AUD (5% reported increased drunkenness). Among individuals in remission from AUD prior to the start of the pandemic, rates of increased drunkenness were 10% for those who were drinking pre-pandemic and 4% for those who had previously been abstinent. Across all groups, women reported nominally greater increases in drunkenness frequency when compared with men, although only women experiencing pre-pandemic AUD symptoms reported significantly greater rates of increased drunkenness since the start of the pandemic compared to men in this group (17% of women vs. 5% of men). Among those without a prior history of AUD, associations between COVID-19 risk and protective factors with increases in drunkenness frequency were not observed. Among all groups with a history of AUD (including those with AUD symptoms and those remitted from AUD), perceived stress was associated with increases in drunkenness. Among the remitted-abstinent group, essential worker status was associated with increases in drunkenness. Gender differences in these associations were observed: among women in the remitted-abstinent group, essential worker status, perceived stress, media consumption, and decreased social interactions were associated with increases in drunkenness. Among men in the remitted-drinking group, perceived stress was associated with increases in drunkenness, and increased relationship quality was associated with decreases in drunkenness. Exploratory analyses indicated that associations between family illness or death with increases in drunkenness and increased relationship quality with decreases in drunkenness were more pronounced among the remitted-drinking participants with higher PRS. Associations between family illness or death, media consumption, and economic hardships with increases in drunkenness and healthy coping with decreases in drunkenness were more pronounced among the remitted-abstinent group with lower interhemispheric alpha EEG connectivity. Our results demonstrated that only individuals with pre-pandemic AUD symptoms reported greater increases in drunkenness frequency since the start of the COVID-19 pandemic compared to those without a lifetime history of AUD. This increase was more pronounced among women than men in this group. However, COVID-19-related stressors and coping activities were associated with changes in the frequency of drunkenness among all groups of participants with a prior history of AUD, including those experiencing AUD symptoms, as well as abstinent and non-abstinent participants in remission. Perceived stress, essential worker status, media consumption, social connections (especially for women), and relationship quality (especially for men) are specific areas of focus for designing intervention and prevention strategies aimed at reducing pandemic-related alcohol misuse among this particularly vulnerable group. Interestingly, these associations were not observed for individuals without a prior history of AUD, supporting prior literature that demonstrates that widespread stressors (e.g., pandemics, terrorist attacks) disproportionately impact the mental health and alcohol use of those with a prior history of problems.

BackgroundSeveral personality traits predict future alcohol problems but also relate to demographic and substance-related variables that themselves correlate with later adverse alcohol outcomes. Few prospective studies have evaluated whether personality measures predict alcohol problems after considering current demographic and substance-related variables.MethodsData from 414 drinkers without alcohol use disorder (AUD) from the Collaborative Study on the Genetics of Alcoholism (average age 20, 44% male) were followed over an average of 9 years. Time 1 (baseline) demography, AUD family history (FH), substance use and problems, and psychiatric histories were gathered using a standardized interview; the Level of Response (LR) to alcohol was measured by the Self-Report of the Effects of alcohol (SRE) questionnaire; and seven personality dimensions were extracted from the NEO Five-Factor Personality, Barratt, and Zuckerman scales. Analyses involved product-moment correlations of each baseline measure with the highest number of DSM-IV AUD criteria endorsed in any follow-up period, and hierarchical regression analyses evaluated whether the personality domains added significantly to the prediction of the outcome after adjusting for other baseline variables.ResultsSignificant correlations with the outcome were observed for baseline age, sex, length of follow-up, AUD family history, past cannabis use, and all alcohol-related baseline variables, including SRE-based LR, but not prior mood or anxiety disorders. All personality characteristics except extraversion also correlated with outcomes. A hierarchical regression analysis that included all relevant personality scores together demonstrated significant contributions to the prediction of future alcohol problems for demographics in Step 1; demographics and most baseline alcohol items, including response level, in Step 2; and cannabis use in Step 3; after which demographics, LR, baseline alcohol problems, cannabis use, and higher sensation seeking added significantly in Step 4. Regression for each personality domain separately revealed significant contributions to Step 4 for all personality domains except openness. Lower levels of response to alcohol added significantly to all regression analyses.ConclusionsMost tested personality scores and lower levels of response to alcohol contributed to predictions of later alcohol problems even after considering baseline demographic and substance use measures.

BackgroundResearchers have identified genetic and neural risk factors for externalizing behaviors. However, it has not yet been determined if genetic liability is conferred in part through associations with more proximal neurophysiological risk markers.MethodsParticipants from the Collaborative Study on the Genetics of Alcoholism, a large, family-based study of alcohol use disorders were genotyped and polygenic scores for externalizing (EXT PGS) were calculated. Associations with target P3 amplitude from a visual oddball task (P3) and broad endorsement of externalizing behaviors (indexed via self-report of alcohol and cannabis use, and antisocial behavior) were assessed in participants of European (EA; N = 2851) and African ancestry (AA; N = 1402). Analyses were also stratified by age (adolescents, age 12-17 and young adults, age 18-32).ResultsThe EXT PGS was significantly associated with higher levels of externalizing behaviors among EA adolescents and young adults as well as AA young adults. P3 was inversely associated with externalizing behaviors among EA young adults. EXT PGS was not significantly associated with P3 amplitude and therefore, there was no evidence that P3 amplitude indirectly accounted for the association between EXT PGS and externalizing behaviors.ConclusionsBoth the EXT PGS and P3 amplitude were significantly associated with externalizing behaviors among EA young adults. However, these associations with externalizing behaviors appear to be independent of each other, suggesting that they may index different facets of externalizing.

Background and hypothesisRisk for cannabis use and schizophrenia is influenced in part by genetic factors, and there is evidence that genetic risk for schizophrenia is associated with subclinical psychotic-like experiences (PLEs). Few studies to date have examined whether genetic risk for schizophrenia is associated with cannabis-related PLEs.Study designWe tested whether measures of cannabis involvement and polygenic risk scores (PRS) for schizophrenia were associated with self-reported cannabis-related experiences in a sample ascertained for alcohol use disorders (AUDs), the Collaborative Study on the Genetics of Alcoholism (COGA). We analyzed 4832 subjects (3128 of European ancestry and 1704 of African ancestry; 42% female; 74% meeting lifetime criteria for an AUD).Study resultsCannabis use disorder (CUD) was prevalent in this analytic sample (70%), with 40% classified as mild, 25% as moderate, and 35% as severe. Polygenic risk for schizophrenia was positively associated with cannabis-related paranoia, feeling depressed or anhedonia, social withdrawal, and cognitive difficulties, even when controlling for duration of daily cannabis use, CUD, and age at first cannabis use. The schizophrenia PRS was most robustly associated with cannabis-related cognitive difficulties (β = 0.22, SE = 0.04, P = 5.2e-7). In an independent replication sample (N = 1446), associations between the schizophrenia PRS and cannabis-related experiences were in the expected direction and not statistically different in magnitude from those in the COGA sample.ConclusionsAmong individuals who regularly use cannabis, genetic liability for schizophrenia-even in those without clinical features-may increase the likelihood of reporting unusual experiences related to cannabis use.

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.

BackgroundParents impact their offspring's brain development, neurocognitive function, risk, and resilience for alcohol use disorder (AUD) via both genetic and socio-environmental factors. Individuals with AUD and their unaffected children manifest low parietal P3 amplitude and low frontal theta (FT) power, reflecting heritable neurocognitive deficits associated with AUD. Likewise, children who experience poor parenting tend to have atypical brain development and greater rates of alcohol problems. Conversely, positive parenting can be protective and critical for normative development of self-regulation, neurocognitive functioning and the neurobiological systems subserving them. Yet, the role of positive parenting in resiliency toward AUD is understudied and its association with neurocognitive functioning and behavioral vulnerability to AUD among high-risk offspring is less known. Using data from the Collaborative Study on the Genetics of Alcoholism prospective cohort (N = 1256, mean age [SD] = 19.25 [1.88]), we investigated the associations of closeness with mother and father during adolescence with offspring P3 amplitude, FT power, and binge drinking among high-risk offspring.MethodsSelf-reported closeness with mother and father between ages 12 and 17 and binge drinking were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism. P3 amplitude and FT power were assessed in response to target stimuli using a Visual Oddball Task.ResultsMultivariate multiple regression analyses showed that closeness with father was associated with larger P3 amplitude (p = 0.002) and higher FT power (p = 0.01). Closeness with mother was associated with less binge drinking (p = 0.003). Among male offspring, closeness with father was associated with larger P3 amplitude, but among female offspring, closeness with mother was associated with less binge drinking. These associations remained statistically significant with father's and mothers' AUD symptoms, socioeconomic status, and offspring impulsivity in the model.ConclusionsAmong high-risk offspring, closeness with parents during adolescence may promote resilience for developing AUD and related neurocognitive deficits albeit with important sex differences.

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.

Some styles of alcohol consumption are riskier than others. How the level and rate of alcohol exposure contribute to the increased risk of alcohol use disorder is unclear, but likely depends on the alcohol concentration time course. We hypothesized that the brain is sensitive to the alcohol concentration rate of change and that people at greater risk would self-administer faster. We developed a novel intravenous alcohol self-administration paradigm to allow participants direct and reproducible control over how quickly their breath alcohol concentration changes. We used drinking intensity and the density of biological family history of alcohol dependence as proxies for risk. Thirty-five alcohol drinking participants aged 21-28 years provided analytical data from a single, intravenous alcohol self-administration session using our computer-assisted alcohol infusion system rate control paradigm. A shorter time to reach 80 mg/dl was associated with increasing multiples of the binge drinking definition (p = 0.004), which was in turn related to higher density of family history of alcoholism (FHD, p = 0.04). Rate-dependent changes in subjective response (intoxication and stimulation) were also associated with FHD (each p = 0.001). Subsequently, given the limited sample size and FHD range, associations between multiples of the binge drinking definition and FHD were replicated and extended in analyses of the Collaborative Study on the Genetics of Alcoholism database. The rate control paradigm models binge and high-intensity drinking in the laboratory and provides a novel way to examine the relationship between the pharmacokinetics and pharmacodynamics of alcohol and potentially the risk for the development of alcohol use disorders.

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).

BackgroundEarly identification of individuals at high risk for alcohol use disorder (AUD) coupled with prompt interventions could reduce the incidence of AUD. In this study, we investigated whether Polygenic Risk Scores (PRS) can be used to evaluate the risk for AUD and AUD severity (as measured by the number of DSM-5 AUD diagnostic criteria met) and compared their performance with a measure of family history of AUD.MethodsWe studied individuals of European ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA). DSM-5 diagnostic criteria were available for 7203 individuals, of whom 3451 met criteria for DSM-IV alcohol dependence or DSM-5 AUD and 1616 were alcohol-exposed controls aged ≥21 years with no history of AUD or drug dependence. Further, 4842 individuals had a positive first-degree family history of AUD (FH+), 2722 had an unknown family history (FH?), and 336 had a negative family history (FH-). PRS were derived from a meta-analysis of a genome-wide association study of AUD from the Million Veteran Program and scores from the problem subscale of the Alcohol Use Disorders Identification Test in the UK Biobank. We used mixed models to test the association between PRS and risk for AUD and AUD severity.ResultsAUD cases had higher PRS than controls with PRS increasing as the number of DSM-5 diagnostic criteria increased (p-values ≤ 1.85E-05 ) in the full COGA sample, the FH+ subsample, and the FH? subsample. Individuals in the top decile of PRS had odds ratios (OR) for developing AUD of 1.96 (95% CI: 1.54 to 2.51, p-value = 7.57E-08 ) and 1.86 (95% CI: 1.35 to 2.56, p-value = 1.32E-04 ) in the full sample and the FH+ subsample, respectively. These values are comparable to previously reported ORs for a first-degree family history (1.91 to 2.38) estimated from national surveys. PRS were also significantly associated with the DSM-5 AUD diagnostic criterion count in the full sample, the FH+ subsample, and the FH? subsample (p-values ≤6.7E-11 ). PRS remained significantly associated with AUD and AUD severity after accounting for a family history of AUD (p-values ≤6.8E-10 ).ConclusionsBoth PRS and family history were associated with AUD and AUD severity, indicating that these risk measures assess distinct aspects of liability to AUD traits.

Genome-wide association studies (GWAS) in admixed populations such as African Americans (AA) have limited sample sizes, resulting in poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located within the boundaries of these genes, we proposed a novel gene-based PRS framework (PRSgene) by using variants located within disease-associated genes. Using the AA GWAS of alcohol use disorder (AUD) from the Million Veteran Program and the EA GWAS of problematic alcohol use as the discovery GWAS, we identified 858 variants from 410 genes that were AUD-related in both AA and EA. PRSgene calculated using these variants were significantly associated with AUD in three AA target datasets (P-values ranged from 7.61E-05 to 6.27E-03; Betas ranged from 0.15 to 0.21) and outperformed PRS calculated using all variants (P-values ranged from 7.28E-03 to 0.16; Betas ranged from 0.06 to 0.18). PRSgene were also associated with AUD in an EA target dataset (P-value = 0.02, Beta = 0.11). In AA, individuals in the highest PRSgene decile had an odds ratio of 1.76 (95% CI: 1.32-2.34) to develop AUD compared to those in the lowest decile. The 410 genes were enriched in 54 Gene Ontology biological processes, including ethanol oxidation and processes involving the synaptic system, which are known to be AUD-related. In addition, 26 genes were targets of drugs used to treat AUD or other diseases that might be considered for repurposing to treat AUD. Our study demonstrated that the gene-based PRS had improved performance in evaluating AUD risk in AA and provided new insight into AUD genetics.

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.

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).

African Americans (AA) have lower prevalence of alcohol dependence and higher subjective response to alcohol than European Americans. Genome-wide association studies (GWAS) have identified genes/variants associated with alcohol dependence specifically in AA; however, the sample sizes are still not large enough to detect variants with small effects. Admixture mapping is an alternative way to identify alcohol dependence genes/variants that may be unique to AA. In this study, we performed the first admixture mapping of DSM-IV alcohol dependence diagnosis, DSM-IV alcohol dependence criterion count, and two scores from the self-rating of effects of ethanol (SRE) as measures of response to alcohol: the first five times of using alcohol (SRE-5) and average of SRE across three times (SRE-T). Findings revealed a region on chromosome 4 that was genome-wide significant for SRE-5 (p value = 4.18E-05). Fine mapping did not identify a single causal variant to be associated with SRE-5; instead, conditional analysis concluded that multiple variants collectively explained the admixture mapping signal. PPARGC1A, a gene that has been linked to alcohol consumption in previous studies, is located in this region. Our finding suggests that admixture mapping is a useful tool to identify genes/variants that may have been missed by current GWAS approaches in admixed populations.

Predictive models have succeeded in distinguishing between individuals with Alcohol use Disorder (AUD) and controls. However, predictive models identifying who is prone to develop AUD and the biomarkers indicating a predisposition to AUD are still unclear. Our sample (n = 656) included offspring and non-offspring of European American (EA) and African American (AA) ancestry from the Collaborative Study of the Genetics of Alcoholism (COGA) who were recruited as early as age 12 and were unaffected at first assessment and reassessed years later as AUD (DSM-5) (n = 328) or unaffected (n = 328). Machine learning analysis was performed for 220 EEG measures, 149 alcohol-related single nucleotide polymorphisms (SNPs) from a recent large Genome-wide Association Study (GWAS) of alcohol use/misuse and two family history (mother DSM-5 AUD and father DSM-5 AUD) features using supervised, Linear Support Vector Machine (SVM) classifier to test which features assessed before developing AUD predict those who go on to develop AUD. Age, gender, and ancestry stratified analyses were performed. Results indicate significant and higher accuracy rates for the AA compared with the EA prediction models and a higher model accuracy trend among females compared with males for both ancestries. Combined EEG and SNP features model outperformed models based on only EEG features or only SNP features for both EA and AA samples. This multidimensional superiority was confirmed in a follow-up analysis in the AA age groups (12-15, 16-19, 20-30) and EA age group (16-19). In both ancestry samples, the youngest age group achieved higher accuracy score than the two other older age groups. Maternal AUD increased the model's accuracy in both ancestries' samples. Several discriminative EEG measures and SNPs features were identified, including lower posterior gamma, higher slow wave connectivity (delta, theta, alpha), higher frontal gamma ratio, higher beta correlation in the parietal area, and 5 SNPs: rs4780836, rs2605140, rs11690265, rs692854, and rs13380649. Results highlight the significance of sampling uniformity followed by stratified (e.g., ancestry, gender, developmental period) analysis, and wider selection of features, to generate better prediction scores allowing a more accurate estimation of AUD development.

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.

The co-occurrence of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) is widely known, yet few studies have examined whether and how AUD symptoms co-occur with PTSD symptom clusters of hypervigilance, avoidance/numbing, and re-experiencing. The purpose of this study was to examine potential overlap between AUD and posttraumatic stress symptomatology, and to characterize the resultant latent classes in terms of demographics, drinking behaviors, parental AUD, and specific traumas experienced (physical violence, sexual violence, and non-assaultive trauma). We hypothesized that classes would be differentiated by type and severity of AUD and PTS symptoms. Drawing from a sample of white and Black participants from the Collaborative Study on the Genetics of Alcoholism (COGA), we examined young adults between the ages of 18-35 who had experienced trauma (N = 2478). A series of LCA models based on the type of trauma experienced, posttraumatic stress symptoms and problematic alcohol use were then fitted to the data. A four-class solution provided the best fit, consisting of a low symptom class (N = 1134), moderate alcohol/low PTS severity (N = 623), mild alcohol/high PTS severity (N = 544), and high symptom severity (N = 177). Higher prevalence of sexual assault was associated with membership in high PTS severity classes, and parent AUD was associated with membership in each class, particularly when the mother or both parents had the disorder. Using person-centered methods such as LCA is a commonsense approach to understanding the heterogeneity of symptoms, trauma types, and individual-level characteristics associated with trauma-exposed individuals and comorbid AUD-PTSD, and our study is one of relatively few to empirically ascertain the co-occurrence of alcohol and PTS symptoms in a high-risk family sample.

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.

IntroductionFamily history (FH) of alcohol dependence is likely to increase the risk of trauma exposure, post-traumatic stress disorder (PTSD), and alcohol dependence. FH of alcohol dependence and trauma has been separately shown to adversely affect planning/problem-solving aspects of executive function. However, few studies have examined these risk factors in an integrated model.MethodsUsing data from trauma-exposed individuals from the Collaborative Study on the Genetics of Alcoholism prospective cohort (N = 1,860), comprising offspring from alcohol-dependent high-risk and comparison families (mean age [SE] = 21.9 [4.2]), we investigated associations of trauma (nonsexual assaultive, nonassaultive, sexual assaultive) with DSM-IV PTSD and alcohol dependence symptom counts, and planning/problem-solving abilities assessed using the Tower of London Test (TOLT). Moderating effects of family history density of alcohol use disorder (FHD) on these associations and sex differences were explored.ResultsFamily history density was positively associated with PTSD in female participants who endorsed a sexual assaultive trauma. Exposure to nonsexual assaultive trauma was associated with more excess moves made on the TOLT.ConclusionFindings from this study demonstrate associations with PTSD and alcohol dependence symptom counts, as well as poor problem-solving ability in trauma-exposed individuals from families densely affected with alcohol dependence, depending on trauma type, FHD, and sex. This suggests that having a FH of alcohol dependence and exposure to trauma during adolescence may be associated with more PTSD and alcohol dependence symptoms, and poor problem-solving abilities in adulthood.

IntroductionFamily history (FH) of alcohol dependence is likely to increase the risk of trauma exposure, post-traumatic stress disorder (PTSD), and alcohol dependence. FH of alcohol dependence and trauma has been separately shown to adversely affect planning/problem-solving aspects of executive function. However, few studies have examined these risk factors in an integrated model.MethodsUsing data from trauma-exposed individuals from the Collaborative Study on the Genetics of Alcoholism prospective cohort (N = 1,860), comprising offspring from alcohol-dependent high-risk and comparison families (mean age [SE] = 21.9 [4.2]), we investigated associations of trauma (nonsexual assaultive, nonassaultive, sexual assaultive) with DSM-IV PTSD and alcohol dependence symptom counts, and planning/problem-solving abilities assessed using the Tower of London Test (TOLT). Moderating effects of family history density of alcohol use disorder (FHD) on these associations and sex differences were explored.ResultsFamily history density was positively associated with PTSD in female participants who endorsed a sexual assaultive trauma. Exposure to nonsexual assaultive trauma was associated with more excess moves made on the TOLT.ConclusionFindings from this study demonstrate associations with PTSD and alcohol dependence symptom counts, as well as poor problem-solving ability in trauma-exposed individuals from families densely affected with alcohol dependence, depending on trauma type, FHD, and sex. This suggests that having a FH of alcohol dependence and exposure to trauma during adolescence may be associated with more PTSD and alcohol dependence symptoms, and poor problem-solving abilities in adulthood.

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.

BackgroundFamily history (FH) is an important risk factor for the development of alcohol use disorder (AUD). A variety of dichotomous and density measures of FH have been used to predict alcohol outcomes; yet, a systematic comparison of these FH measures is lacking. We compared 4 density and 4 commonly used dichotomous FH measures and examined variations by gender and race/ethnicity in their associations with age of onset of regular drinking, parietal P3 amplitude to visual target, and likelihood of developing AUD.MethodsData from the Collaborative Study on the Genetics of Alcoholism (COGA) were utilized to compute the density and dichotomous measures. Only subjects and their family members with DSM-5 AUD diagnostic information obtained through direct interviews using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA) were included in the study. Area under receiver operating characteristic curves were used to compare the diagnostic accuracy of FH measures at classifying DSM-5 AUD diagnosis. Logistic and linear regression models were used to examine associations of FH measures with alcohol outcomes.ResultsDensity measures had greater diagnostic accuracy at classifying AUD diagnosis, whereas dichotomous measures presented diagnostic accuracy closer to random chance. Both dichotomous and density measures were significantly associated with likelihood of AUD, early onset of regular drinking, and low parietal P3 amplitude, but density measures presented consistently more robust associations. Further, variations in these associations were observed such that among males (vs. females) and Whites (vs. Blacks), associations of alcohol outcomes with density (vs. dichotomous) measures were greater in magnitude.ConclusionsDensity (vs. dichotomous) measures seem to present more robust associations with alcohol outcomes. However, associations of dichotomous and density FH measures with different alcohol outcomes (behavioral vs. neural) varied across gender and race/ethnicity. These findings have great applicability for alcohol research examining FH of AUD.

Genome-wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM-IV AD (primary analysis), DSM-IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans-ancestral meta-analyses combined these results with data from 3175 (585 families) African-American (AA) individuals from COGA. In the EA GWAS, three loci were genome-wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E-11) and Desire to cut drinking (P = 1.21E-11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E-09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E-08). In the trans-ancestral meta-analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome-wide significant: rs61826952 (chromosome 1, DSM-IV AD, P = 8.42E-11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E-08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P

Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P

Event related oscillations (EROs) are heritable measures of neurocognitive function that have served as useful phenotype in genetic research. A recent family genome-wide association study (GWAS) by the Collaborative Study on the Genetics of Alcoholism (COGA) found that theta EROs during visual target detection were associated at genome-wide levels with several single nucleotide polymorphisms (SNPs), including a synonymous SNP, rs702859, in the KCNJ6 gene that encodes GIRK2, a G-protein inward rectifying potassium channel that regulates excitability of neuronal networks. The present study examined the effect of the KCNJ6 SNP (rs702859), previously associated with theta ERO to targets in a visual oddball task, on theta EROs during reward processing in a monetary gambling task. The participants were 1601 adolescent and young adult offspring within the age-range of 17-25years (800 males and 801 females) from high-dense alcoholism families as well as control families of the COGA prospective study. Theta ERO power (3.5-7.5Hz, 200-500ms post-stimulus) was compared across genotype groups. ERO theta power at central and parietal regions increased as a function of the minor allele (A) dose in the genotype (AA>AG>GG) in both loss and gain conditions. These findings indicate that variations in the KCNJ6 SNP influence magnitude of theta oscillations at posterior loci during the evaluation of loss and gain, reflecting a genetic influence on neuronal circuits involved in reward-processing. Increased theta power as a function of minor allele dose suggests more efficient cognitive processing in those carrying the minor allele of the KCNJ6 SNPs. Future studies are needed to determine the implications of these genetic effects on posterior theta EROs as possible "protective" factors, or as indices of delays in brain maturation (i.e., lack of frontalization).

BackgroundIndividuals at high risk to develop alcoholism often manifest neurocognitive deficits as well as increased impulsivity. The goal of the present study is to elucidate reward processing deficits, externalizing disorders, and impulsivity as elicited by electrophysiological, clinical and behavioral measures in subjects at high risk for alcoholism from families densely affected by alcoholism in the context of brain maturation across age groups and gender.MethodsEvent-related potentials (ERPs) and current source density (CSD) during a monetary gambling task (MGT) were measured in 12-25 year old offspring (N=1864) of families in the Collaborative Study on the Genetics of Alcoholism (COGA) Prospective study; the high risk (HR, N=1569) subjects were from families densely affected with alcoholism and the low risk (LR, N=295) subjects were from community families. Externalizing disorders and impulsivity scores were also compared between LR and HR groups.ResultsHR offspring from older (16-25 years) male and younger (12-15 years) female subgroups showed lower P3 amplitude than LR subjects. The amplitude decrement was most prominent in HR males during the loss condition. Overall, P3 amplitude increase at anterior sites and decrease at posterior areas were seen in older compared to younger subjects, suggesting frontalization during brain maturation. The HR subgroups also exhibited hypofrontality manifested as weaker CSD activity during both loss and gain conditions at frontal regions. Further, the HR subjects had higher impulsivity scores and increased prevalence of externalizing disorders. P3 amplitudes during the gain condition were negatively correlated with impulsivity scores.ConclusionsOlder male and younger female HR offspring, compared to their LR counterparts, manifested reward processing deficits as indexed by lower P3 amplitude and weaker CSD activity, along with higher prevalence of externalizing disorders and higher impulsivity scores.SignificanceReward related P3 is a valuable measure reflecting neurocognitive dysfunction in subjects at risk for alcoholism, as well as to characterize reward processing and brain maturation across gender and age group.

BackgroundIndividuals at high risk to develop alcoholism often manifest neurocognitive deficits as well as increased impulsivity. Event-related oscillations (EROs) have been used to effectively measure brain (dys)function during cognitive tasks in individuals with alcoholism and related disorders and in those at risk to develop these disorders. The current study examines ERO theta power during reward processing as well as impulsivity in adolescent and young adult subjects at high risk for alcoholism.MethodsEROs were recorded during a monetary gambling task (MGT) in 12-25 years old participants (N = 1821; males = 48%) from high risk alcoholic families (HR, N = 1534) and comparison low risk community families (LR, N = 287) from the Collaborative Study on the Genetics of Alcoholism (COGA). Impulsivity scores and prevalence of externalizing diagnoses were also compared between LR and HR groups.ResultsHR offspring showed lower theta power and decreased current source density (CSD) activity than LR offspring during loss and gain conditions. Younger males had higher theta power than younger females in both groups, while the older HR females showed more theta power than older HR males. Younger subjects showed higher theta power than older subjects in each comparison. Differences in topography (i.e., frontalization) between groups were also observed. Further, HR subjects across gender had higher impulsivity scores and increased prevalence of externalizing disorders compared to LR subjects.ConclusionsAs theta power during reward processing is found to be lower not only in alcoholics, but also in HR subjects, it is proposed that reduced reward-related theta power, in addition to impulsivity and externalizing features, may be related in a predisposition to develop alcoholism and related disorders.

Genome-wide association studies (GWAS) of electroencephalographic endophenotypes for alcohol use disorder (AUD) has identified noncoding polymorphisms within the KCNJ6 gene. KCNJ6 encodes GIRK2, a subunit of a G-protein-coupled inwardly rectifying potassium channel that regulates neuronal excitability. We studied the effect of upregulating KCNJ6 using an isogenic approach with human glutamatergic neurons derived from induced pluripotent stem cells (male and female donors). Using multielectrode arrays, population calcium imaging, single-cell patch-clamp electrophysiology, and mitochondrial stress tests, we find that elevated GIRK2 acts in concert with 7-21 d of ethanol exposure to inhibit neuronal activity, to counteract ethanol-induced increases in glutamate response, and to promote an increase intrinsic excitability. Furthermore, elevated GIRK2 prevented ethanol-induced changes in basal and activity-dependent mitochondrial respiration. These data support a role for GIRK2 in mitigating the effects of ethanol and a previously unknown connection to mitochondrial function in human glutamatergic neurons. [ABSTRACT FROM AUTHOR]

Contemporary genome-wide association study (GWAS) methods typically do not account for variability in genetic effects throughout development. We applied genomic structural equation modeling to combine developmentally-informative phenotype data and GWAS to create polygenic scores (PGS) for alcohol use frequency that are specific to developmental stage. Longitudinal cohort studies targeted for gene-identification analyses include the Collaborative Study on the Genetics of Alcoholism (adolescence n = 1,118, early adulthood n = 2,762, adulthood n = 5,255), the National Longitudinal Study of Adolescent to Adult Health (adolescence n = 3,089, early adulthood n = 3,993, adulthood n = 5,149), and the Avon Longitudinal Study of Parents and Children (ALSPAC; adolescence n = 5,382, early adulthood n = 3,613). PGS validation analyses were conducted in the COGA sample using an alternate version of the discovery analysis with COGA removed. Results suggest that genetic liability for alcohol use frequency in adolescence may be distinct from genetic liability for alcohol use frequency later in developmental periods. The age-specific PGS predicts an increase of 4 drinking days per year per PGS standard deviation when modeled separately from the common factor PGS in adulthood. The current work was underpowered at all steps of the analysis plan. Though small sample sizes and low statistical power limit the substantive conclusions that can be drawn regarding these research questions, this work provides a foundation for future genetic studies of developmental variability in the genetic underpinnings of alcohol use behaviors and genetically-informed, age-matched phenotype prediction. [ABSTRACT FROM AUTHOR]