Correlates of suicidal behaviors and genetic risk among United States veterans with schizophrenia or bipolar I disorder.

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals.

Genomic risk for post-traumatic stress disorder in families densely affected with alcohol use disorders.

Recent genome-wide association studies (GWAS) have identified genetic markers of post-traumatic stress disorder (PTSD) in civilian and military populations. However, studies have yet to examine the genetics of PTSD while factoring in risk for alcohol dependence, which commonly co-occur. We examined genome-wide associations for DSM-IV PTSD among 4,978 trauma-exposed participants (31% with alcohol dependence, 50% female, 30% African ancestry) from the Collaborative Study on the Genetics of Alcoholism (COGA). We also examined associations of polygenic risk scores (PRS) derived from the Psychiatric Genomics Consortium (PGC)-PTSD Freeze 2 (N = 3533) and Million Veterans Program GWAS of PTSD (N = 5200) with PTSD and substance dependence in COGA, and moderating effects of sex and alcohol dependence. 7.3% of COGA participants met criteria for PTSD, with higher rates in females (10.1%) and those with alcohol dependence (12.3%). No independent loci met genome-wide significance in the PTSD meta-analysis of European (EA) and African ancestry (AA) participants. The PGC-PTSD PRS was associated with increased risk for PTSD (B = 0.126, p < 0.001), alcohol dependence (B = 0.231, p < 0.001), and cocaine dependence (B = 0.086, p < 0.01) in EA individuals. A significant interaction was observed, such that EA individuals with alcohol dependence and higher polygenic risk for PTSD were more likely to have PTSD (B = 0.090, p < 0.01) than those without alcohol dependence. These results further support the importance of examining substance dependence, specifically alcohol dependence, and PTSD together when investigating genetic influence on these disorders.

Mapping potential pathways from polygenic liability through brain structure to psychological problems across the transition to adolescence.

BACKGROUND: We used a polygenic score for externalizing behavior (extPGS) and structural MRI to examine potential pathways from genetic liability to conduct problems via the brain across the adolescent transition. METHODS: Three annual assessments of child conduct problems, attention-deficit/hyperactivity problems, and internalizing problems were conducted across across 9-13 years of age among 4,475 children of European ancestry in the Adolescent Brain Cognitive DevelopmentSM Study (ABCD Study®). RESULTS: The extPGS predicted conduct problems in each wave (R2 = 2.0%-2.9%). Bifactor models revealed that the extPRS predicted variance specific to conduct problems (R2 = 1.7%-2.1%), but also variance that conduct problems shared with other measured problems (R2 = .8%-1.4%). Longitudinally, extPGS predicted levels of specific conduct problems (R2 = 2.0%), but not their slope of change across age. The extPGS was associated with total gray matter volume (TGMV; R2 = .4%) and lower TGMV predicted both specific conduct problems (R2 = 1.7%-2.1%) and the variance common to all problems in each wave (R2 = 1.6%-3.1%). A modest proportion of the polygenic liability specific to conduct problems in each wave was statistically mediated by TGMV. CONCLUSIONS: Across the adolescent transition, the extPGS predicted both variance specific to conduct problems and variance shared by all measured problems. The extPGS also was associated with TGMV, which robustly predicted conduct problems. Statistical mediation analyses suggested the hypothesis that polygenic variation influences individual differences in brain development that are related to the likelihood of conduct problems during the adolescent transition, justifying new research to test this causal hypothesis.

Patterns and predictors of alcohol misuse trajectories from adolescence through early midlife.

We took a multilevel developmental contextual approach and characterized trajectories of alcohol misuse from adolescence through early midlife, examined genetic and environmental contributions to individual differences in those trajectories, and identified adolescent and young adult factors associated with change in alcohol misuse. Data were from two longitudinal population-based studies. FinnTwin16 is a study of Finnish twins assessed at 16, 17, 18, 25, and 35 years (N = 5659; 52% female; 32% monozygotic). The National Longitudinal Study of Adolescent to Adult Health (Add Health) is a study of adolescents from the United States, who were assessed at five time points from 1994 to 2018 (N = 18026; 50% female; 64% White, 21% Black, 4% Native American, 7% Asian, 9% Other race/ethnicity). Alcohol misuse was measured as frequency of intoxication in FinnTwin16 and frequency of binge drinking in Add Health. In both samples, trajectories of alcohol misuse were best described by a quadratic growth curve: Alcohol misuse increased across adolescence, peaked in young adulthood, and declined into early midlife. Individual differences in these trajectories were primarily explained by environmental factors. Several adolescent and young adult correlates were related to the course of alcohol misuse, including other substance use, physical and mental health, and parenthood.

Moral foundations, moral emotions, and moral distress in NICU nurses.

Background: Moral distress is common in neonatal intensive care unit (NICU) nurses. Purpose: The purpose of this study was to evaluate the relationships between NICU nurses' moral foundations, moral emotions, and moral distress. Research design and method: This is an observational cross-sectional self-report questionnaire study. Participants and research context: One hundred and forty-two (24%) of 585 Level 3-4 NICU nurses completed pen-and-paper self-report measures of moral foundations (harm, fairness, ingroup, authority, and purity) (Moral Foundations Questionnaire-20), proneness to self-conscious moral emotions (guilt and shame) (modified Personal Feelings Questionnaire-2), and moral distress (futile care, compromised care, and untruthful care) (modified Revised Moral Distress Scale). Ethical considerations: Participation was voluntary and anonymous. The ethics committees of the participating hospitals approved the study protocol (HREC Reference: LNR/18/SCHN/316). Results: Non-parametric statistical analyses showed medium to large correlations between moral foundations and moral emotions. Moral foundations and moral emotions had trivial to small correlations with moral distress. Using a liberal p-value of <.10 for statistical significance because of the small sample size, harm (rs = 0.22) and fairness (rs = 0.16) predicted futile care, ingroup predicted compromised care (rs = 0.19) and untruthful care (rs = 0.15), and purity predicted untruthful care (rs = 0.15). Guilt-proneness predicted futile care (rs = 0.15). Shame-proneness did not predict moral distress. Conclusion: The correlations between moral foundations and moral emotions were significant. Moral foundations and guilt-proneness predicted one or more dimensions of moral distress. The smaller than expected effect sizes may have been owing to how moral foundations, moral emotions, and moral distress were conceptualized and measured, or to moral disengagement, including NICU nurses' possible reluctance to countenance aversive but morally warranted feelings of guilt and especially shame. Understanding the nature of these relationships may complement the efforts of NICU administrators, educators, counsellors, and nurses themselves to mitigate moral distress.

Relationships of nursing stress and trait emotional intelligence with mental health in neonatal intensive care unit nurses: A cross-sectional correlational study.

BACKGROUND: The neonatal intensive care unit (NICU) is a stressful and emotionally laden environment, but the relationships between nursing stress, emotional intelligence, and mental health have not been studied in NICU nurses. OBJECTIVES: The study aimed to determine (i) whether nursing stress and trait emotional intelligence controlled for the five-factor model of personality predict mental health in NICU nurses and (ii) whether trait emotional intelligence buffers the effect of nursing stress on mental health. METHODS: A cross-sectional correlational study in 123 (28%) of 440 eligible NICU nurses using self-report questionnaire measures of nursing stress (Nursing Stress Scale), trait emotional intelligence (Assessing Emotions Scale), and psychological distress and emotional well-being (Mental Health Inventory). The data were analysed using hierarchical multiple regression and moderation analyses. RESULTS: The hierarchical multiple regressions showed nursing stress predicted psychological distress (ΔR2 = .11) and emotional well-being (ΔR2 = .10) at Step 1. The five-factor model of personality explained further variance in psychological distress (ΔR2 = .27) and emotional well-being (ΔR2 = .26) at Step 2. Finally, trait emotional intelligence predicted further increments in psychological distress (ΔR2 = .05) and emotional well-being (ΔR2 = .08) at Step 3. The optimism (expecting good things to occur in one's life) and mood regulation (dampening, repairing and maintaining emotions) subdimension of trait emotional intelligence predicted psychological distress (ß = -.29) and emotional well-being (ß = .41) in the final models of the hierarchical multiple regressions. Trait emotional intelligence did not moderate the effect of nursing stress on psychological distress or emotional well-being. CONCLUSIONS: NICU managers and educators should seek to remedy controllable work-related stressors and support NICU nurses' emotional competence because these respective environmental and personal factors predict mental health in these nurses.

Guidelines for Evaluating the Comparability of Down-Sampled GWAS Summary Statistics.

Proprietary genetic datasets are valuable for boosting the statistical power of genome-wide association studies (GWASs), but their use can restrict investigators from publicly sharing the resulting summary statistics. Although researchers can resort to sharing down-sampled versions that exclude restricted data, down-sampling reduces power and might change the genetic etiology of the phenotype being studied. These problems are further complicated when using multivariate GWAS methods, such as genomic structural equation modeling (Genomic SEM), that model genetic correlations across multiple traits. Here, we propose a systematic approach to assess the comparability of GWAS summary statistics that include versus exclude restricted data. Illustrating this approach with a multivariate GWAS of an externalizing factor, we assessed the impact of down-sampling on (1) the strength of the genetic signal in univariate GWASs, (2) the factor loadings and model fit in multivariate Genomic SEM, (3) the strength of the genetic signal at the factor level, (4) insights from gene-property analyses, (5) the pattern of genetic correlations with other traits, and (6) polygenic score analyses in independent samples. For the externalizing GWAS, although down-sampling resulted in a loss of genetic signal and fewer genome-wide significant loci; the factor loadings and model fit, gene-property analyses, genetic correlations, and polygenic score analyses were found robust. Given the importance of data sharing for the advancement of open science, we recommend that investigators who generate and share down-sampled summary statistics report these analyses as accompanying documentation to support other researchers' use of the summary statistics.

Clinical, environmental, and genetic risk factors for substance use disorders: characterizing combined effects across multiple cohorts.

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.

A multivariate approach to understanding the genetic overlap between externalizing phenotypes and substance use disorders.

Substance use disorders (SUDs) are phenotypically and genetically correlated with each other and with other psychological traits characterized by behavioural under-control, termed externalizing phenotypes. In this study, we used genomic structural equation modelling to explore the shared genetic architecture among six externalizing phenotypes and four SUDs used in two previous multivariate genome-wide association studies of an externalizing and an addiction risk factor, respectively. We first evaluated five confirmatory factor analytic models, including a common factor model, alternative parameterizations of two-factor structures and a bifactor model. We next explored the genetic correlations between factors identified in these models and other relevant psychological traits. Finally, we quantified the degree of polygenic overlap between externalizing and addiction risk using MiXeR. We found that the common and two-factor structures provided the best fit to the data, evidenced by high factor loadings, good factor reliability and no evidence of concerning model characteristics. The two-factor models yielded high genetic correlations between factors (rg s ≥ 0.87), and between the effect sizes of genetic correlations with external traits (rg  ≥ 0.95). Nevertheless, 21 of the 84 correlations with external criteria showed small, significant differences between externalizing and addiction risk factors. MiXer results showed that approximately 81% of influential externalizing variants were shared with addiction risk, whereas addiction risk shared 56% of its influential variants with externalizing. These results suggest that externalizing and addiction genetic risk are largely shared, though both constructs also retain meaningful unshared genetic variance. These results can inform future efforts to identify specific genetic influences on externalizing and SUDs.

Military service and risk of subsequent drug use disorders among Swedish men.

PURPOSE: Environmental factors contribute substantially to risk for drug use disorders (DUD). The current study applies multiple methods to empirically test whether military service is associated with subsequent DUD, as previous findings are inconsistent. METHODS: Longitudinal Swedish national registry data on a cohort of male conscripts born 1972-1987 (maximum N = 485,900) were used to test the association between military service and subsequent registration for DUD. Cox proportional hazard models were used in preliminary analyses, followed by three methods that enable causal inference: propensity score models, co-relative models, and instrumental variable analysis. RESULTS: Across all methods, military service was causally associated with lower risk of DUD. Hazard ratios ranged from HR = 0.43 (95% confidence intervals [CI] 0.37; 0.50) in the instrumental variable analysis to 0.77 (0.75; 0.79) in the multivariate propensity score matching analysis. This effect diminished across time. In the model including a propensity score, HRs remained below 1 across the observation period, while confidence intervals included 1 after ~ 11 years in the co-relative analysis and after ~ 21 years in the instrumental variable analysis. CONCLUSIONS: In this cohort of Swedish men, complementary methods indicate that military service conferred substantial but time-limited protection against subsequent DUD. The observed effect could be due to reduced opportunity for substance use during service, social cohesion experienced during and after service, and/or socioeconomic advantages among veterans. Additional research is necessary to clarify these protective mechanisms and determine how other environmental contexts can provide similar benefits.

The Associations of Polygenic Scores for Risky Behaviors and Parenting Behaviors with Adolescent Externalizing Problems.

The current study focused on longitudinal effects of genetics and parental behaviors and their interplay on externalizing behaviors in a panel study following individuals from adolescence to young adulthood. The nationally representative sample of Add Health participants of European ancestry included N = 4142 individuals, measured on three occasions. Parenting was operationalized as experiences with child maltreatment and maternal closeness. Externalizing problems were operationalized as alcohol use, cannabis use, and antisocial behaviors. Genetic effects were operationalized as a polygenic score (PGS) of risky behaviors. The results showed significant effects for child maltreatment, maternal closeness, and PGS, above and beyond other factors and previous levels of externalizing behaviors. Furthermore, maternal closeness was found to negatively correlate with PGS. No significant interaction effects of parenting and PGS were found. The results underscore the joint independent effects of parenting and genetics on the change in externalizing behaviors from adolescence to young adulthood.

Principal Component Analysis Reduces Collider Bias in Polygenic Score Effect Size Estimation.

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

Genes regulating levels of ω-3 long-chain polyunsaturated fatty acids are associated with alcohol use disorder and consumption, and broader externalizing behavior in humans.

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

Exploring the relationships between adolescent alcohol misuse and later life health outcomes.

BACKGROUND: We sought to clarify the impact of adolescent alcohol misuse on adult physical health and subjective well-being. To do so, we investigated both the direct associations between adolescent alcohol misuse and early midlife physical health and life satisfaction and the indirect effects on these outcomes attributable to subsequent alcohol problems. METHOD: The sample included 2733 twin pairs (32% monozygotic; 52% female) from the FinnTwin16 study. Adolescent alcohol misuse was a composite of frequency of drunkenness, frequency of alcohol use, and alcohol problems at ages 16, 17, and 18.5. The early midlife outcomes included somatic symptoms, self-rated health, and life satisfaction at age 34. The mediators examined as part of the indirect effect analyses included alcohol problems from the Rutgers Alcohol Problem Index at ages 24 and 34. Serial mediation and co-twin comparison models were applied and included covariates from adolescence and early midlife. RESULTS: There were weak direct associations between adolescent alcohol misuse and early midlife physical health and life satisfaction. However, there was stronger evidence for indirect effects, whereby young adult and early midlife alcohol problems serially mediated the relationship between adolescent alcohol misuse and early midlife somatic symptoms (ß = 0.03, 95% CI [0.03, 0.04]), self-rated health (ß = -0.02, 95% CI [-0.03, -0.01]), and life satisfaction (ß = -0.03, CI [-0.04, -0.02]). These serial mediation effects were robust in co-twin comparison analyses. CONCLUSIONS: These results provide evidence that alcohol problems are a primary driver linking adolescent alcohol misuse and poor health outcomes across the lifespan.

The role of parental genotype in the intergenerational transmission of externalizing behavior: Evidence for genetic nurturance.

The purpose of this study was to examine possible pathways by which genetic risk associated with externalizing is transmitted in families. We used molecular data to disentangle the genetic and environmental pathways contributing to adolescent externalizing behavior in a sample of 1,111 adolescents (50% female; 719 European and 392 African ancestry) and their parents from the Collaborative Study on the Genetics of Alcoholism. We found evidence for genetic nurture such that parental externalizing polygenic scores were associated with adolescent externalizing behavior, over and above the effect of adolescents' own externalizing polygenic scores. Mediation analysis indicated that parental externalizing psychopathology partly explained the effect of parental genotype on children's externalizing behavior. We also found evidence for evocative gene-environment correlation, whereby adolescent externalizing polygenic scores were associated with lower parent-child communication, less parent-child closeness, and lower parental knowledge, controlling for parental genotype. These effects were observed among participants of European ancestry but not African ancestry, likely due to the limited predictive power of polygenic scores across ancestral background. These results demonstrate that in addition to genetic transmission, genes influence offspring behavior through the influence of parental genotypes on their children's environmental experiences, and the role of children's genotypes in shaping parent-child relationships.

Dimensions of the Burnout Measure: Relationships with shame- and guilt-proneness in neonatal intensive care unit nurses.

BACKGROUND: Burnout in neonatal intensive care unit (NICU) nurses has been correlated with personality proneness to shame. However, the structural validities of the one-factor Burnout Measure (BM) and the two-factor Personal Feelings Questionnaire-2 (PFQ-2) used to assess burnout and shame-proneness, respectively, in these nurses were not evaluated. OBJECTIVES: The aim of the study was (i) to perform factor analyses of the BM and the PFQ-2 and (ii) to determine the relationships of burnout dimensions retrieved by factor analysis with similarly validated dimensions of shame- and guilt-proneness in NICU nurses. METHODS: This is a multicentre cross-sectional cohort study that involved 142 (24%) of 585 NICU nurses who were currently providing direct newborn care in six level 3-4 NICUs in New South Wales, Australia. RESULTS: The BM was a multidimensional measure of burnout composed of three latent factors: Demoralisation, exhaustion, and loss of motive. Based on burnout dimension mean scores of 4 or more, worryingly high levels of Demoralisation, Exhaustion, and Loss of Motive were reported by 21%, 84%, and 24% of nurses, respectively. Shame and Guilt together explained 41%, 9%, and 15% of the variance in Demoralisation, Exhaustion, and Loss of Motive, respectively. Shame controlled for guilt made respective large and moderate contributions to the variance in Demoralisation (ß = .62, p < .001) and Loss of Motive (ß = .33, p < .001). Guilt moderated the effect of Shame on Loss of Motive (ΔR2 = .031, p = .027). CONCLUSIONS: Factor analysis of the BM showed burnout in NICU nurses was a multidimensional syndrome comprising exhaustion, Demoralisation, and loss of motive. Worryingly high levels of exhaustion, Demoralisation, and loss of motive were not uncommon. The Demoralisation dimension had a strong correlation with shame-proneness. Understanding the nature of Demoralisation and the phenomenology of shame and guilt should be psychoeducational components of the holistic management of burnout in NICU nurses.

Mapping Pathways by Which Genetic Risk Influences Adolescent Externalizing Behavior: The Interplay Between Externalizing Polygenic Risk Scores, Parental Knowledge, and Peer Substance Use.

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.

Associations of Alcohol Consumption With Epigenome-Wide DNA Methylation and Epigenetic Age Acceleration: Individual-Level and Co-twin Comparison Analyses.

BACKGROUND: DNA methylation may play a role in the progression from normative to problematic drinking and underlie adverse health outcomes associated with alcohol misuse. We examined the association between alcohol consumption and DNA methylation patterns using 3 approaches: a conventional epigenome-wide association study (EWAS); a co-twin comparison design, which controls for genetic and environmental influences that twins share; and a regression of age acceleration, defined as a discrepancy between chronological age and DNA methylation age, on alcohol consumption. METHODS: Participants came from the Finnish Twin Cohorts (FinnTwin12/FinnTwin16; N = 1,004; 55% female; average age = 23 years). Individuals reported the number of alcoholic beverages consumed in the past week, and epigenome-wide DNA methylation was assessed in whole blood using the Infinium HumanMethylation450 BeadChip. RESULTS: In the EWAS, alcohol consumption was significantly related to methylation at 24 CpG sites. When evaluating whether differences between twin siblings (185 monozygotic pairs) in alcohol consumption predicted differences in DNA methylation, co-twin comparisons replicated 4 CpG sites from the EWAS and identified 23 additional sites. However, when we examined qualitative differences in drinking patterns between twins (heavy drinker vs. light drinker/abstainer or moderate drinker vs. abstainer; 44 pairs), methylation patterns did not significantly differ within twin pairs. Finally, individuals who reported higher alcohol consumption also exhibited greater age acceleration, though results were no longer significant after controlling for genetic and environmental influences shared by co-twins. CONCLUSIONS: Our analyses offer insight into the associations between epigenetic variation and levels of alcohol consumption in young adulthood.

Predicting Alcohol Dependence Symptoms by Young Adulthood: A Co-Twin Comparisons Study.

Co-twin comparisons address familial confounding by controlling for genetic and environmental influences that twin siblings share. We applied the co-twin comparison design to investigate associations of adolescent factors with alcohol dependence (AD) symptoms. Participants were 1286 individuals (581 complete twin pairs; 42% monozygotic; and 54% female) from the FinnTwin12 study. Predictors included adolescent academic achievement, substance use, externalizing problems, internalizing problems, executive functioning, peer environment, physical health, relationship with parents, alcohol expectancies, life events, and pubertal development. The outcome was lifetime AD clinical criterion count, as measured in young adulthood. We examined associations of each adolescent domain with AD symptoms in individual-level and co-twin comparison analyses. In individual-level analyses, adolescents with higher levels of substance use, teacher-reported externalizing problems at age 12, externalizing problems at age 14, self- and co-twin-reported internalizing problems, peer deviance, and perceived difficulty of life events reported more symptoms of AD in young adulthood (ps < .044). Conversely, individuals with higher academic achievement, social adjustment, self-rated health, and parent-child relationship quality met fewer AD clinical criteria (ps < .024). Associations between adolescent substance use, teacher-reported externalizing problems, co-twin-reported internalizing problems, peer deviance, self-rated health, and AD symptoms were of a similar magnitude in co-twin comparisons. We replicated many well-known adolescent correlates of later alcohol problems, including academic achievement, substance use, externalizing and internalizing problems, self-rated health, and features of the peer environment and parent-child relationship. Furthermore, we demonstrate the utility of co-twin comparisons for understanding pathways to AD. Effect sizes corresponding to the associations between adolescent substance use, teacher-reported externalizing problems, co-twin-reported internalizing problems, peer deviance, and self-rated health were not significantly attenuated (p value threshold = .05) after controlling for genetic and environmental influences that twin siblings share, highlighting these factors as candidates for further research.

A Family-Based Genome Wide Association Study of Externalizing Behaviors.

Shared genetic factors contribute to the high degree of comorbidity among externalizing problems (e.g. substance use and antisocial behavior). We leverage this common genetic etiology to identify genetic influences externalizing problems in participants from the Collaborative Study on the Genetics of Alcoholism (European ancestry = 7568; African ancestry = 3274). We performed a family-based genome-wide association study (GWAS) on externalizing scores derived from criterion counts of five DSM disorders (alcohol dependence, alcohol abuse, illicit drug dependence, illicit drug abuse, and either antisocial personality disorder or conduct disorder). We meta analyzed these results with a similar measure of externalizing in an independent sample, Spit for Science (combined sample N = 15,112). We did not discover any robust genome-wide significant signals. Polygenic scores derived from the ancestry-specific GWAS summary statistics predicted externalizing problems in an independent European ancestry sample, but not in those of African ancestry. However, these PRS were no longer significant after adjusting for multiple testing. Larger samples with deep phenotyping are necessary for the discovery of SNPs related to externalizing problems.