John Kramer

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.

The conventional understanding of how genetic factors impact risk for alcohol use disorder (AUD) typically focuses on how one’s own genetic predispositions influence the likelihood of experiencing clinically significant problems with alcohol (direct genetic effects). Yet, in close relationships like marriage, a spouse’s genotype may function as part of the target individual’s environment through its influence on spousal behaviors and experiences, termed social genetic effect. We examined social genetic effects on AUD in 660 opposite-sex spousal dyads from the Collaborative Study on the Genetics of Alcoholism, restricting analyses to individuals who were genetically similar to European reference panels. Measured and latent indicators of genetic risk included polygenic scores of problematic alcohol use (PGSPAU) and parental history of AUD (PHAUD), respectively. The outcome was DSM-5 alcohol use disorder criteria count (AUDsx) during marriage. 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 a higher PGSPAU was associated with greater AUDsx (B = .08, 95%CI [0.035, 0.132]). This social genetic effect was robust after controlling for both partners’ educational attainment. Spousal PHAUD was not associated with AUDsx. Exploratory analyses indicated that the social genetic effect of partner PGSPAU was stronger for males. 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.

Objective. Parental separation and parental relationship discord are cross-sectionally associated with alcohol use behaviors in youth and adults, but less is known about whether and how parental separation and discord are associated with the longitudinal course of alcohol misuse behaviors (i.e., trajectories), and how these family stressors interact with genetic predispositions. The purpose of this project was to examine how the longitudinal course of heavy episodic drinking across adolescence and young adulthood varied as a function of polygenic risk, parental separation, and parental relationship discord.Methods. Participants included genetically inferred continental groups of European (EA, N=1761) and African (AA, N=894) American from the Collaborative Study on the Genetics of Alcoholism (COGA) Prospective sample who were reassessed biennially (M = 4.65 assessments). Alcohol misuse was indexed by frequency of heavy episodic drinking during the past year. Predictors included parental separation, parental relationship discord, and problematic alcohol use polygenic scores (PGSPAU). Data were analyzed with linear mixed effects growth models. Results. Heavy episodic drinking frequency increased between adolescence and young adulthood and then decreased. Among EA participants, parental separation was associated with heavy episodic drinking intercepts, but was not related to linear slope or quadratic curvature of the course. Higher PGSPAU was associated with a faster initial growth and slower decline in the longitudinal course of heavy episodic drinking. Among AA participants, parental relationship discord was not associated with heavy episodic drinking at baseline but was associated with a faster initial growth and slower decline later on. No interaction was found between PGSPAU and parental separation and discord for predicting heavy episodic drinking trajectories in either EA or AA samples. Discussion. Genetic risk and exposure to parental separation and discord are associated with the course of heavy episodic drinking trajectories from adolescence through young adulthood, with some differences across continental groups.

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.

Importance: Both current DSM-5 diagnoses of substance use disorders (SUDs) and the recent “preaddiction” conceptual proposal (i.e., mild-to-moderate SUD) rely on criterion count-based approaches, without consideration of evidence regarding varying severity grading indexed by individual criteria. Objective: To examine correlates of alcohol use disorder (AUD) across count-based severity groups (i.e., mild, moderate, mild-to-moderate, severe), identify specific diagnostic criteria indicative of greater severity, and evaluate whether the presence of specific criteria within mild-to-moderate AUD differentiates across relevant correlates and manifests in greater hazards of severe AUD development. Design: Cross-sectional and longitudinal cohort study. Setting: Family-based study of individuals from seven sites across the United States. Participants: Cross-sectional ( N =13,110; mean [SD] age, 37.8 [14.2] years) and longitudinal cohorts ( N =2,818; mean baseline [SD] age, 16.1 [3.2] years) from the Collaborative Study on the Genetics of Alcoholism (COGA). Exposure: N/A Main Outcomes and Measures: Sociodemographic, alcohol-related, psychiatric comorbidity (major depressive disorder, antisocial personality disorder, and other SUDs), brain electroencephalography (EEG), and AUD polygenic score measures as correlates of DSM-5 AUD levels (i.e., mild, moderate, severe) and criterion severity-defined “preaddiction” (i.e., low-risk vs. high-risk mild-to-moderate) AUD diagnostic groups. Results: Associations with alcohol-related, psychiatric, EEG, and AUD polygenic score measures reinforced the role of increasing criterion counts as indexing severity. Yet even within those meeting criteria for mild-to-moderate AUD (2-5 criteria), the presence of specific “high-risk” criteria (e.g., 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 one “high-risk” criterion outperformed other adolescent and young adult correlates of AUD progression (i.e., comorbid psychiatric diagnoses, alcohol involvement milestones) and was associated with more accelerated progression to severe AUD (adjusted hazard ratio [aHR], 11.62; 95% CI, 7.54-17.92) compared to 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 Relevance: Current count-based AUD diagnostic approaches and the “preaddiction” concept both ignore heterogeneity among criteria. Estimating addiction vulnerability by emphasizing specific “high-risk” criteria may improve our understanding of its development and focus attention on those at greatest risk. Key Points: Question: Does emphasis on specific alcohol use disorder (AUD) criteria improve identification of individuals at risk for developing more severe AUD? Findings: Individuals meeting criteria for mild-to-moderate AUD are two-fold more likely to progress to severe AUD if they endorse criteria for drinking despite physical/psychological problems, giving up important activities, spending a great deal of time drinking, failure to fulfill major role obligations, withdrawal, and craving, even after accounting for total criterion count. Meaning: Emphasis on especially severe criteria as indicators of addiction vulnerability in current diagnostic approaches may increase detection of individuals with greater likelihood for disorder progression.

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.

Background: Several 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.Methods: Data 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.Results: Significant 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.Conclusions: Most 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.

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

Background: Parents 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.Methods: Self‐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.Results: Multivariate 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.Conclusions: Among high‐risk offspring, closeness with parents during adolescence may promote resilience for developing AUD and related neurocognitive deficits albeit with important sex differences.