Kathleen K. Bucholz

Background: The widespread prevalence of alcohol use disorder (AUD) and availability of treatments contrasts with limited treatment utilization. Here, in the Collaborative Studies on the Genetics of Alcoholism (COGA), we examined the extent to which genetic factors (i.e., family‐based heritability ( h ² _GCTA ), polygenic scores [PGS]) are associated with individual differences in AUD treatment utilization that could be leveraged to target intervention efforts. Methods: Non‐proband COGA participants with a lifetime Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM‐5) AUD diagnosis, whose genomic ancestry resembled that of European (EUR‐like: N = 3148; 370 nuclear families; 222 extended family pedigrees) and African (AFR‐like: N = 962; 92 nuclear families; 79 extended family pedigrees) reference panels were selected for analyses. AUD treatment h ² _GCTA and associations with PGS (i.e., alcohol involvement, cigarette use, psychopathology, externalizing behavior, and cognition‐related) were estimated, along with between‐ and within‐family effects of the PGSs. Results: AUD treatment was heritable ( h ² _GCTA = 0.36; SE = 0.06) and positively associated with PGS for problematic alcohol use, drinks/week, externalizing behavior, depression, anxiety and schizophrenia/bipolar (ORs > 1.12) while being negatively associated with education attainment (OR = 0.90) in the EUR‐like sample after accounting for AUD severity ( p _FDR ≤ 0.04). When all significant PGSs were simultaneously included, only alcohol PGSs remained significant. There were no significant PGS associations in within‐family analyses. Despite a nominally significant positive association with cigarettes per day, no PGSs were associated with AUD treatment following FDR adjustment in the AFR‐like sample. Conclusions: Genetic factors underlying alcohol use influence AUD treatment utilization, but this phenotype is largely not significantly associated with current estimates of polygenic scores for other complex traits; this suggests a potential unique genetic etiology requiring further investigation with a genome‐wide association study. The lack of significant within‐family PGS associations may have likely arisen from power reductions due to restricting the sample to full siblings. Together, these findings highlight potential facets influencing the underutilization of AUD treatment.

Background: Marital transitions and stability are key social determinants of alcohol use, yet their impact across different life stages remains underexplored. This study utilizes a lifespan‐oriented approach to examine longitudinal associations between marital status and alcohol consumption and problems and to investigate underlying sex differences. Methods: Longitudinal data from two components (early mid‐life and later‐life) of the Collaborative Study on the Genetics of Alcoholism (COGA) were included, with participants averaging 33 (early mid‐life) and 62 (later‐life) years of age at their last interview. Participants were categorized into distinct groups based on their marital history across assessment waves: persistently married (reference), never married, divorced/separated, widowed, and three transition groups (into marriage, out of marriage, and mixed transitions). Alcohol use measures included past 12‐month alcohol symptom counts, past 6‐month typical drinks per week, and past 6‐month maximum drinks consumed in 24 h. Generalized linear mixed models estimated cohort‐specific risks. Results: Across both cohorts, alcohol consumption declined with age, while AUD symptom counts significantly increased ( p < 0.001). In the later‐life sample, never married individuals exhibited the highest likelihood of AUD symptoms (IRR = 3.82, p < 0.001). A significant sex interaction indicated widowhood was associated with a threefold increase in AUD symptoms (IRR = 3.46, p = 0.003), whereas widowhood was relatively protective among women (reference group). In the early mid‐life sample, transitioning out of marriage emerged as a primary correlate of symptom escalation (IRR = 2.13, p < 0.001). Conclusion: Marital stability buffers against AUD problems across the lifespan. However, the risks associated with marital instability are highly specific: marital exit poses a critical threat in early mid‐life, while widowhood represents a profound vulnerability for older men. Interventions should be tailored with attention to life stage and sex‐specific risks to mitigate alcohol‐related harm during marital transitions.

Background: Research suggests that multiple genetically influenced pathways of risk impact alcohol use disorder (AUD), including externalizing (disinhibition, behavioral undercontrol), internalizing (negative affect, depression), and alcohol‐specific (physiological response to alcohol) factors. This study examined the joint effects of genetic influences representing these risk domains on AUD and their influence on comorbid phenotypes among individuals with AUD. Methods: Participants of European‐like ancestry from the Collaborative Study on the Genetics of Alcoholism ( N = 6883) provided data on lifetime AUD, conduct disorder (CD), antisocial personality disorder (ASPD), major depressive disorder (MDD), alcohol expectancies, sensation seeking, and neuroticism. Polygenic scores (PGS) representing externalizing (EXT), major depressive disorder (MDD), and alcohol‐specific (ALC‐sp) risk were calculated. First, participants were grouped based on combinations of high versus low (top vs. bottom 30%) EXT, MDD, and ALC‐sp PGS ( n = 2006), and AUD outcomes were compared across groups. Second, among individuals with AUD, psychopathology, alcohol expectancies, sensation seeking, and neuroticism were compared across those with high versus low EXT ( n = 1664), MDD ( n = 1620), and ALC‐sp ( n = 1669) PGS. Results: Participants with three high PGS and those with high EXT + high ALC‐sp PGS had the most severe AUD outcomes. High EXT + high MDD PGS and high MDD + high ALC‐sp PGS groups generally did not differ from groups with only one high PGS. Comparisons between groups with only one high PGS were not significant. Among individuals with AUD, high EXT PGS was associated with CD/ASPD, arousal/aggression alcohol expectancies, and relaxation/tension reduction alcohol expectancies; high MDD PGS was associated with MDD and neuroticism. Conclusions: Quantity and type of genetic risk are important for AUD outcomes. EXT plays an outsized role in AUD, particularly in the presence of other high PGS, and may potentiate alcohol expectancies that reinforce harmful patterns of use. Findings elucidate the role of multiple pathways of genetic risk for AUD and how they impact comorbid phenotypes.

Gradients across socioeconomic status (SES) exist across most health conditions. While there has been significant attention devoted to the relationship between SES and physical and mental health, less research has examined how these relate to substance use disorders (SUD). In the current study, we use data from the prospective study within the Collaborative Study on the Genetics of Alcoholism (COGA) to explore the relationship between SES (in early life and adulthood) with multiple substance use disorders (alcohol, tobacco, cannabis, opioid, cocaine, and other substances). We find that early life SES (parental education and income) are associated with lower odds of lifetime diagnoses and lower severity for tobacco (TUD) and cannabis (CUD) use disorders. Associations with TUD remain after adjusting for demographic and familial risk, but associations with CUD were null after including familial risk factors. In participants aged 25+, adult education was associated with lower odds of diagnosis and severity for each of the SUD considered, conditional on early life SES, adult income, sociodemographic characteristics, and familial risk for SUD. Exploratory analyses of changes in SES revealed that those who were upwardly or downwardly mobile were at the lowest or greatest risk for more severe SUD across multiple substances, respectively. Our results demonstrate the relevance of both early life and adult SES in SUD risk. Early life conditions seem particularly relevant for specific substances while greater adult education was associated with reduced risk across all forms of SUDs.

Background: The field's conventional understanding of how genetic factors impact risk for alcohol use disorder (AUD) typically focuses on direct genetic effects, or how an individual's own genetic predispositions are associated with the likelihood of experiencing clinically significant alcohol problems. More recently, studies of behavioral health outcomes in preclinical and human studies have demonstrated the potential importance of social genetic effects or the influence of a social partner's genotype on substance use and related outcomes. In this study, we sought to characterize social genetic effects for AUD, specifically in the context of marriage. Methods: The sample included 660 opposite‐sex spousal dyads from the Collaborative Study on the Genetics of Alcoholism, restricted to individuals who were genetically similar to European reference panels. Measured and latent indicators of genetic risk included polygenic scores of problematic alcohol use (PGS _PAU ) and parental history of AUD (PH _AUD ), respectively. The outcome was Diaganostic and Statistical Manual (DSM)‐5 alcohol use disorder criterion count (AUDcrit) during marriage. Multilevel models accounted for the non‐independence of partners' data, including correlations between partners' genetic risk and residual covariance in AUDcrit. Results: After accounting for direct genetic effects (i.e., the influence of one's own genetic predispositions) and the correlations between partners' genetic predispositions, we found that having a spouse with higher PGS _PAU was associated with higher AUDcrit (B = 0.084, 95% CI [0.035, 0.132]). This social genetic effect was robust after adjusting for both partners' educational attainment. Spousal PH _AUD was not associated with AUDcrit. Exploratory analyses indicated that the social genetic effect of spousal PGS _PAU was stronger among male target individuals. Conclusions: Findings highlight the potential importance of social genetic effects for understanding the pathways from genotype to alcohol use disorder and the need for further investigation of latent measures of genetic predispositions in studies of social genetic effects.

Background: Romantic relationships are important contexts for substance use and emotional well-being. We tested the hypotheses that (i) genetic predispositions for alcohol consumption would be positively associated with partner substance use, (ii) partner substance use would moderate genetic influences on one’s own alcohol outcomes, and (iii) partner discordance in substance use would be associated with lower emotional well-being and relationship quality. Methods: Analyses included 2,357 participants (M _age = 51.4, 58.2% female) from the Collaborative Studies on the Genetics of Alcoholism. Focal measures included participants’ reports of their own and their current partner’s past-year substance use (frequencies of alcohol use, heavy drinking, drunkenness, cannabis use, and nicotine use), emotional well-being, and relationship quality. Participants’ genetic predispositions were indexed with genome-wide polygenic scores for alcohol consumption (PGS _Alc ). Participant–partner substance use discordance was calculated as the difference between the participant’s and their partner’s use for each substance use measure, separately. Results: Participant PGS _Alc was not significantly associated with partners’ perceived substance use. Frequent perceived partner alcohol use and heavy drinking significantly amplified the association between PGS _Alc and alcohol use or drunkenness. Frequent perceived partner drunkenness and cannabis use significantly attenuated the association between PGS _Alc and heavy drinking or frequency of alcohol use. Participant–partner discordance for several substance use measures was significantly associated with lower emotional well-being and relationship quality, controlling for participant and partner substance use main effects. Conclusions: The results highlight the importance of partner substance use in etiological models of alcohol use, emotional health outcomes, and relationship quality.

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.

Obsessive-compulsive disorder (OCD) affects ∼1% of children and adults and is partly caused by genetic factors. We conducted a genome-wide association study (GWAS) meta-analysis combining 53,660 OCD cases and 2,044,417 controls and identified 30 independent genome-wide significant loci. Gene-based approaches identified 249 potential effector genes for OCD, with 25 of these classified as the most likely causal candidates, including WDR6, DALRD3, CTNND1 and multiple genes in the MHC region. We estimated that ∼11,500 genetic variants explained 90% of OCD genetic heritability. OCD genetic risk was associated with excitatory neurons in the hippocampus and cortex, along with D1- and D2-type dopamine receptor-containing medium spiny neurons. OCD genetic risk was shared with 65 of 112 additional phenotypes, including all of the psychiatric disorders we examined. In particular, OCD shared genetic risk with anxiety, depression, anorexia nervosa, and Tourette syndrome, and was negatively associated with inflammatory bowel diseases, educational attainment, and body mass index.

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.