Differences in genetic correlations between posttraumatic stress disorder and alcohol-related problems phenotypes compared to alcohol consumption-related phenotypes.

BACKGROUND: Posttraumatic Stress Disorder (PTSD) tends to co-occur with greater alcohol consumption as well as alcohol use disorder (AUD). However, it is unknown whether the same etiologic factors that underlie PTSD-alcohol-related problems comorbidity also contribute to PTSD- alcohol consumption. METHODS: We used summary statistics from large-scale genome-wide association studies (GWAS) of European-ancestry (EA) and African-ancestry (AA) participants to estimate genetic correlations between PTSD and a range of alcohol consumption-related and alcohol-related problems phenotypes. RESULTS: In EAs, there were positive genetic correlations between PTSD phenotypes and alcohol-related problems phenotypes (e.g. Alcohol Use Disorders Identification Test (AUDIT) problem score) (rGs: 0.132-0.533, all FDR adjusted p < 0.05). However, the genetic correlations between PTSD phenotypes and alcohol consumption -related phenotypes (e.g. drinks per week) were negatively associated or non-significant (rGs: -0.417 to -0.042, FDR adjusted p: <0.05-NS). For AAs, the direction of correlations was sometimes consistent and sometimes inconsistent with that in EAs, and the ranges were larger (rGs for alcohol-related problems: -0.275 to 0.266, FDR adjusted p: NS, alcohol consumption-related: 0.145-0.699, FDR adjusted p: NS). CONCLUSIONS: These findings illustrate that the genetic associations between consumption and problem alcohol phenotypes and PTSD differ in both strength and direction. Thus, the genetic factors that may lead someone to develop PTSD and high levels of alcohol consumption are not the same as those that lead someone to develop PTSD and alcohol-related problems. Discussion around needing improved methods to better estimate heritabilities and genetic correlations in diverse and admixed ancestry samples is provided.

A Polygenic Risk Score Enhances Risk Prediction for Adolescents' Antisocial Behavior over the Combined Effect of 22 Extra-familial, Familial, and Individual Risk Factors in the Context of the Family Check-Up.

Possessing informative tools to predict who is most at risk for antisocial behavior in adolescence is important to help identify families most in need of early intervention. Polygenic risk scores (PRSs) have been shown to predict antisocial behavior, but it remains unclear whether PRSs provide additional benefit above more conventional tools to early risk detection for antisocial behavior. This study examined the utility of a PRS in predicting adolescents' antisocial behavior after accounting for a broad index of children's contextual and individual risk factors for antisocial behavior. Participants were drawn from a longitudinal family-based prevention study (N = 463; Ncontrol = 224; 48.8% girls; 45.1% White; 30.2% Black; 12.7% Hispanic/Latino, 10.4% biracial; 0.2% Native American). Participants were recruited from US-based Women, Infants, and Children Nutritional Supplement programs. A risk tolerance PRS was created from a genome-wide association study. We created a robust measure capturing additive effects of 22 conventional measures of a risk of antisocial behavior assessed at child age 2 (before intervention). A latent variable capturing antisocial behavior (ages 10.5-16) was created. After accounting for intervention status and the conventional risk index, the risk tolerance PRS predicted independent variance in antisocial behavior. A PRS-by-conventional risk interaction showed that the conventional risk measure only predicted antisocial behavior at high levels of the PRS. Thus, the risk tolerance PRS provides unique predictive information above conventional screening tools and, when combined with them, identified a higher-risk subgroup of children. Integrating PRSs could facilitate risk identification and, ultimately, prevention screening, particularly in settings unable to serve all individuals in need.

The effect of parental alcohol use on alcohol use disorder in young adulthood: Exploring the mediating roles of adolescent alcohol expectancies and consumption.

INTRODUCTION: Parental alcohol use and problems are risk factors for alcohol use disorder (AUD), and these effects may be mediated by adolescent alcohol expectancies and consumption. In the present study, we tested the direct effects of mothers' and fathers' alcohol consumption on young adult AUD, as well as the indirect effects through adolescent maximum alcohol use, alcohol consumption, and alcohol expectancies. METHODS: Participants were 5160 individuals (49.1% female) and their biological parents from the Avon Longitudinal Study of Parents and Children, a cohort study of children born in southwestern England during 1991 and 1992. Structural equation modeling (SEM) was used to test associations of mothers' and fathers' alcohol use (assessed when children were 12 years old) with age 24 AUD. Potential mediator variables included the maximum number of alcoholic drinks consumed within a 24-h period by age 13.5 and alcohol expectancies and alcohol consumption at ages 17 and 20. RESULTS: Higher maternal and paternal alcohol use were associated with higher levels of alcohol consumption at age 17. Greater alcohol consumption, in turn, was related to a more severe presentation of AUD. The overall indirect effects of mothers' (b = 0.033, 95% confidence interval [CI] = 0.006, 0.059) and fathers' drinking (b = 0.041, 95% CI = 0.018, 0.064) on AUD were modest but significant, and were primarily comprised of adolescent alcohol consumption rather than alcohol expectancies. CONCLUSIONS: Our findings underscore the importance of both mothers' and fathers' drinking for the development of alcohol use and problems across adolescence and young adulthood.

Developmental genetic effects on externalizing behavior and alcohol use: Examination across two longitudinal samples.

Externalizing behavior in early adolescence is associated with alcohol use in adolescence and early adulthood and these behaviors often emerge as part of a developmental sequence. This pattern can be the result of heterotypic continuity, in which different behaviors emerge over time based on an underlying shared etiology. In particular, there is largely a shared genetic etiology underlying externalizing and substance use behaviors. We examined whether polygenic risk for alcohol use disorder predicted (1) externalizing behavior in early adolescence and alcohol use in adolescence in the Early Steps Multisite sample and (2) externalizing behavior in adolescence and alcohol use in early adulthood in the Project Alliance 1 (PAL1) sample. We examined associations separately for African Americans and European Americans. When examining European Americans in the Early Steps sample, greater polygenic risk was associated with externalizing behavior in early adolescence. In European Americans in PAL1, we found greater polygenic risk was associated with alcohol use in early adulthood. Effects were largely absent in African Americans in both samples. Results imply that genetic predisposition for alcohol use disorder may increase risk for externalizing and alcohol use as these behaviors emerge developmentally.

Psychiatric Resilience and Alcohol Resistance: A Twin Study of Genetic Correlation and Sex Differences.

Variability in psychiatric response following stressful/traumatic life events is frequently observed. There is also variability in propensity for alcohol use disorder (AUD) such that some can consume substantial amounts and not develop AUD symptoms whereas others develop an AUD. Our group has applied discrepancy-based approaches to capture psychiatric resilience (PR) and alcohol resistance (AR), both moderately heritable. This study sought to (1) examine the genetic and environmental correlation of these constructs and (2) model qualitative and quantitative sex effects. Data came from a large twin sample (N = 4501 twin pairs) with self-report measures and interviews assessing distress symptoms, stressful life events, alcohol use, and AUD. Correlated liability model results suggested a moderate degree of genetic correlation between PR and AR (0.54) due to the same genetic factors in males and females. Findings highlight the shared genetic predisposition of these resilience/resistance constructs while emphasizing the impact of unique environmental experiences.

Potential causal effect of posttraumatic stress disorder on alcohol use disorder and alcohol consumption in individuals of European descent: A Mendelian Randomization Study.

BACKGROUND: Posttraumatic stress disorder (PTSD) often co-occurs with alcohol consumption (AC) and alcohol use disorder (AUD). However, it is unknown whether the same etiologic influences that underlie PTSD co-occurring with AUD are those that underlie PTSD and AC individually. METHODS: This study used large-scale genome-wide association study (GWAS) data to test whether PTSD and drinks per week [DPW]/AUD are causally related to one another, and, if so, whether PTSD precedes DPW/AUD and/or vice versa. We used Mendelian Randomization methods to analyze European ancestry GWAS summary statistics from the Psychiatric Genomics Consortium (PGC; PTSD), GWAS & Sequencing Consortium of Alcohol and Nicotine Use (GSCAN; DPW), and the Million Veteran Program (MVP; AUD). RESULTS: PTSD exerted a potentially causal effect on AUD (ß = 0.039, SE = 0.014, p = 0.005), but not on DPW (ß = 0.002, SE = 0.003, p = 0.414). Additionally, neither DPW (ß = 0.019, SE = 0.041, p = 0.637) nor AUD (ß = 8.87 × 10-4 , SE = 0.001, p = 0.441) exerted a causal effect on PTSD. CONCLUSIONS: These findings are consistent with the self-medication model, in which individuals misuse alcohol to cope with aversive trauma-related symptoms. These findings extend latent analysis and molecular findings of shared and correlated risk between PTSD and alcohol phenotypes. Given the health behaviors associated with these phenotypes, these findings are important in that they suggest groups to prioritize for prevention efforts. Further, they provide a rationale for future preclinical and clinical studies examining the biological mechanisms by which PTSD may impact AUD.

Longitudinal Examination of the Impact of Resilience and Stressful Life Events on Alcohol Use Disorder Outcomes.

Stressful life events (SLEs) are a risk factor for alcohol use problems, and there is a need for identification of factors that may offset this risk. Resilience is uniquely, inversely associated with alcohol use, but there remains a dearth of research examining the buffering effect of resilience toward alcohol use problems in the context of SLEs. Objectives: This study used prospective data from an epidemiological twin sample (N = 7441) to test whether resilience at Time 1 would act as a buffer for new onset SLEs (e.g. assault, marital problems) against risk for alcohol dependence (AD) symptoms at Time 2. Results: The final model, adjusted for familial relatedness and controlling for demographic covariates and Time 1 (lifetime) AD symptoms, identified significant main effects of resilience and SLEs; those with greater resilience at Time 1 reported fewer symptoms (ß=-.087, p<.001) and those with greater new-onset SLEs reported greater symptoms (ß=.116, p<.001) at Time 2. However, there was no significant interaction (ß=-.008, p>.05). Conclusions: Although findings further support the association of resilience and SLEs with AD, results do not support the conceptualization of resilience as a buffer against the impact of future life stressors on alcohol use outcomes. This suggests other factors may be more relevant for understanding protective factors for alcohol use problems or the relation between resilience and SLEs on alcohol use outcomes.

Meta-Analysis of Associations Between Hypothalamic-Pituitary-Adrenal Axis Genes and Risk of Posttraumatic Stress Disorder.

The hypothalamic-pituitary-adrenal (HPA) axis has been of interest in attempts to identify genetic vulnerability for posttraumatic stress disorder (PTSD). Although numerous HPA-axis genes have been implicated in candidate gene studies, the findings are mixed and interpretation is limited by study design and methodological inconsistencies. To address these inconsistencies in the PTSD candidate gene literature, we conducted meta-analyses of HPA-related genes from both a traditional single nucleotide polymorphism (SNP)-level analysis and a gene-level analysis, using novel methods aggregating markers in the same gene. Database searches (PubMed and PsycINFO) identified 24 unique articles examining six HPA-axis genes in PTSD; analyses were conducted on four genes (ADCYAP1R1, CRHR1, FKBP5, NR3C1) that met study eligibility criteria (original research, human subjects, main effect association study of selected genes, PTSD as an outcome, trauma-exposed control group) and had sufficient data and number of studies for use in meta-analysis, within 20 unique articles. Findings from SNP-level analyses indicated that two variants (rs9296158 in FKBP5 and rs258747 in NR3C1) were nominally associated with PTSD, ps = .001 and .001, respectively, following multiple testing correction. At the gene level, significant relations between PTSD and both NR3C1 and FKBP5 were detected and robust to sensitivity analyses. Although study limitations exist (e.g., varied outcomes, inability to test moderators), taken together, these results provide support for FKBP5 and NR3C1 in risk for PTSD. Overall, this work highlights the utility of meta-analyses in resolving discrepancies in the literature and the value of adopting gene-level approaches to investigate the etiology of PTSD.

Offspring Self-Disclosure Predicts Substance-Related Outcomes in an Emergency Department Sample of Young Adults with Traumatic Injury.

BACKGROUND: Hundreds of thousands of individuals visit the emergency department (ED) every year, with many visits occurring following alcohol misuse. Parent-child relationship factors are associated with alcohol-related outcomes. For example, offspring choice to self-disclose information about their lives to parents, rather than parents actively soliciting this information, is associated with substance use. However, it is unclear whether self-disclosure uniquely predicts alcohol-related outcomes in a young adult ED sample. METHODS: Data were collected from young adults (age 18-30 years) visiting an ED for a traumatic injury (n=79). Participants were about 24.4 years old, majority male (53.7%), and Caucasian (76%; 24% African-American). A bifactor model within a structural equation model tested unique effects of self-disclosure on age at first drink, propensity for risky drinking, and likelihood of consuming substances prior to ED visit, over and above parental solicitation and a general factor and gender. RESULTS: Those who shared more information with their caregivers reported an older age at first drink, lower propensity for risky drinking and lower propensity to consume substances prior to their ED visit. CONCLUSIONS: These findings suggest that self-disclosure may be a unique risk factor in the initiation of alcohol use, development of problem use, and consequences following use.

Impulsivity and Comorbid PTSD and Binge Drinking.

OBJECTIVE: Trauma exposure is common, with estimates of 28% to 90% of adults reporting at least one traumatic event over their lifetime. Those exposed to traumatic events are at risk for alcohol misuse (i.e., binge drinking), posttraumatic stress disorder (PTSD), or both. A potential underlying mechanism for this comorbidity is increased impulsivity-the tendency to act rashly. Little work to date has examined the impact of different impulsogenic traits on this comorbidity. METHODS: This study (n = 162) investigated trauma-exposed young adults (aged 21-30) who had endorsed a lifetime interpersonal trauma. In addition, three impulsogenic traits (motor, nonplanning, and attentional) were measured. RESULTS: Over and above the covariates for age, gender, race, and traumatic events, greater attentional impulsivity was associated with greater likelihood of meeting criteria for PTSD and binge drinking, compared to meeting criteria for PTSD, binge drinking, or neither. Neither nonplanning impulsivity nor motor impulsivity exerted unique effects. CONCLUSIONS: Young adults who report difficulty attending to immediate stimuli within their environment may be unable to think about and/or process the traumatic event, potentially increasing risk for PTSD and maladaptive coping skills to manage this distress (e.g., alcohol misuse, binge drinking).

The Relationship Between Experiences With the Criminal Justice System and Mental Health Outcomes Among Survivors of Homicide.

Homicide survivors are at increased risk for mental health disorders, including depression, posttraumatic stress disorder (PTSD), and complicated grief (CG). Accordingly, this survey study examined how satisfaction with the criminal justice system (CJS) was associated with depression, PTSD, and CG among 47 homicide survivors. It also examined how satisfaction with specific aspects of the CJS related to satisfaction with the overall CJS. Satisfaction with the overall CJS was uniquely associated with depression (odds ratio [OR] = 2.32; 95% confidence interval [CI] [1.16, 4.66]) while satisfaction with the police department was uniquely associated with CG (OR = 2.14; 95% CI [1.02, 4.47]). Satisfaction with having input into the CJS process and satisfaction with efforts devoted by the CJS to apprehend the perpetrator were uniquely related to satisfaction with the overall CJS (ß = .49, p = .003 and ß = .40, p = .007, respectively).

The Effects of a BDNF Val66Met Polymorphism on Posttraumatic Stress Disorder: A Meta-Analysis.

OBJECTIVE: Given evidence that posttraumatic stress disorder (PTSD) is moderately heritable, a number of studies utilizing candidate gene approaches have attempted to examine the potential contributions of theoretically relevant genetic variation. Some of these studies have found sup port for a brain-derived neurotrophic factor (BDNF) variant, Val66Met, in the risk of developing PTSD, while others have failed to find this link. METHODS: This study sought to reconcile these conflicting findings using a meta-analysis framework. Analyses were also used to determine whether there is significant heterogeneity in the link between this variant and PTSD. We conducted a systematic review of the literature on BDNF and PTSD from the PsycINFO and PubMed databases. A total of 11 studies were included in the analysis. RESULTS: Findings indicate a marginally significant effect of the BDNF Val66Met variant on PTSD (p < 0.1). However, of the 11 studies included, only 2 suggested an effect with a non-zero confidence interval, one of which showed a z score of 3.31. We did not find any evidence for heterogeneity. CONCLUSIONS: Findings from this meta-analytic investigation of the published literature provide little support for the Val66Met variant of BDNF as a predictor of PTSD. Future well-powered agnostic genome-wide association studies with more refined phenotyping are needed to clarify genetic influences on PTSD.

Parent and peer influences on emerging adult substance use disorder: A genetically informed study.

The present study utilizes longitudinal data from a high-risk community sample to examine the unique effects of genetic risk, parental knowledge about the daily activities of adolescents, and peer substance use on emerging adult substance use disorders (SUDs). These effects are examined over and above a polygenic risk score. In addition, this polygenic risk score is used to examine gene-environment correlation and interaction. The results show that during older adolescence, higher adolescent genetic risk for SUDs predicts less parental knowledge, but this relation is nonsignificant in younger adolescence. Parental knowledge (using mother report) mediates the effects of parental alcohol use disorder (AUD) and adolescent genetic risk on risk for SUD, and peer substance use mediates the effect of parent AUD on offspring SUD. Finally, there are significant gene-environment interactions such that, for those at the highest levels of genetic risk, less parental knowledge and more peer substance use confers greater risk for SUDs. However, for those at medium and low genetic risk, these effects are attenuated. These findings suggest that the evocative effects of adolescent genetic risk on parenting increase with age across adolescence. They also suggest that some of the most important environmental risk factors for SUDs exert effects that vary across level of genetic propensity.

Genetic and psychosocial predictors of alcohol use trajectories among disaster-exposed adolescents.

BACKGROUND AND OBJECTIVES: Adolescent alcohol misuse is associated with numerous long-term adverse outcomes, so we examined predictors of alcohol use among disaster-exposed adolescents, a group at-risk for alcohol misuse. METHODS: The current study (n = 332) examined severity of tornado-related exposure, posttraumatic stress disorder (PTSD) symptoms, emotional support, and a genetic risk sum score (GRSS) as predictors of alcohol use trajectories. RESULTS: Severity of exposure interacted with the GRSS to predict both intercept (12-month follow up quantity of alcohol use) and growth rate. Emotional support also interacted with adolescent PTSD symptoms to predict intercept and growth rate. DISCUSSION AND CONCLUSIONS: Adolescents with greater severity of disaster exposure and high genetic risk comprise a high risk group, on which efforts to prevent alcohol use should be focused. Additionally, emotional support is essential in buffering the effects of PTSD symptoms on alcohol use outcomes among adolescents. SCIENTIFIC SIGNIFICANCE: Toward the aim of reducing adolescent alcohol misuse following disaster exposure, there is utility in inserting immediate supports (e.g., basic resources) into communities/families that have experienced significant disaster-related severity, particularly among adolescents at high levels of genetic risk for alcohol use/misuse. Additionally, prevention efforts aimed at improving emotional supports for adolescents with more PTSD symptoms may reduce propensity for alcohol misuse following disaster. This information can be easily incorporated into existing web-based interventions. (Am J Addict 2017;26:623-631).

Association of Posttraumatic Stress Disorder With rs2267735 in the ADCYAP1R1 Gene: A Meta-Analysis.

Recent studies point to the potential role of the (pituitary) adenylate cyclase activating polypeptide receptor 1 (ADCYAP1R1) gene, which has been implicated in stress response, in posttraumatic stress disorder (PTSD). Multiple genetic association studies have examined potential PTSD risk related to this gene, with mixed results. We conducted a meta-analysis of rs2267735 in ADCYAP1R1 in PTSD. A literature search was conducted using PubMed and PsycINFO, resulting in nine studies that met criteria for inclusion in analysis. Biostat's Comprehensive Meta-Analysis was used to conduct the main meta-analysis on the combined sex sample, as well as two subanalyses examining effects separately in female and male participants. Results indicated that the C allele of rs2267735 conferred significant risk for PTSD in the combined sex data, OR = 1.210, 95% CI [1.007, 1.454], p = .042, and in the subsample of women and girls, OR = 1.328, 95% CI [1.026, 1.719], p = .031; but not in the subsample of men and boys, OR = 0.964, 95% CI [0.733, 1.269], p = .796. These results provide evidence for an association between ADCYAP1R1 and PTSD and indicate that there may indeed be sex differences. Implications of these findings, including the role of rs2267735 as one modulator of the stress system, are discussed.

Affiliation with substance-using peers: Examining gene-environment correlations among parent monitoring, polygenic risk, and children's impulsivity.

Parental monitoring can buffer the effect of deviant peers on adolescents' substance use by reducing affiliation with substance-using peers. However, children's genetic predispositions may evoke poorer monitoring, contributing to negative child outcomes. We examined evocative genotype-environment correlations underlying children's genetic predisposition for behavioral undercontrol and parental monitoring in early adolescence via children's impulsivity in middle childhood, and the influence of parental monitoring on affiliation with substance-using peers a year and a half later (n = 359). Genetic predisposition for behavioral undercontrol was captured using a polygenic risk score, and a portion of passive rGE was controlled by including parents' polygenic risk scores. Children's polygenic risk predicted poorer parental monitoring via greater children's impulsivity, indicating evocative rGE, controlling for a portion of passive rGE. Poorer parental monitoring predicted greater children's affiliation with substance-using peers a year and a half later. Results are discussed with respect to gene-environment correlations within developmental cascades.

Reducing sexual risk behaviors: secondary analyses from a randomized controlled trial of a brief web-based alcohol intervention for underage, heavy episodic drinking college women.

BACKGROUND: Alcohol use and sexual risk behaviors (SRBs) are significant problems on college campuses. College women are at particularly high risk for negative consequences associated with sexually transmitted infections (STIs) and unwanted pregnancy. METHODS: The current study (n = 160) examined the effect of a brief, web-based alcohol intervention (n = 53) for college women on reducing SRBs compared to an assessment only control (n = 107) with a randomized controlled trial. Outcome measures included condom use assertiveness and number of vaginal sex partners and data were collected at baseline and three-month follow-up. RESULTS: Regression analyses revealed that the alcohol intervention was associated with higher levels of condom use assertiveness at a three-month follow-up. Additionally, more alcohol use was associated with less condom use assertiveness for those with more significant sexual assault histories. CONCLUSIONS: These findings suggest that alcohol interventions may impact college women's beliefs but not behavior, and future interventions should more explicitly target both alcohol and sexual risk to decrease risky behaviors.

Predicting substance use in emerging adulthood: A genetically informed study of developmental transactions between impulsivity and family conflict.

Deviance proneness models propose a multilevel interplay in which transactions among genetic, individual, and family risk factors place children at increased risk for substance use. We examined bidirectional transactions between impulsivity and family conflict from middle childhood to adolescence and their contributions to substance use in adolescence and emerging adulthood (n = 380). Moreover, we examined children's, mothers', and fathers' polygenic risk scores for behavioral undercontrol, and mothers' and fathers' interparental conflict and substance disorder diagnoses as predictors of these transactions. The results support a developmental cascade model in which children's polygenic risk scores predicted greater impulsivity in middle childhood. Impulsivity in middle childhood predicted greater family conflict in late childhood, which in turn predicted greater impulsivity in late adolescence. Adolescent impulsivity subsequently predicted greater substance use in emerging adulthood. Results are discussed with respect to evocative genotype-environment correlations within developmental cascades and applications to prevention efforts.

The Interactive Effects of Effort to Regulate Alcohol Use, Anxiety Disorders, and Affective Disorders on Long-Term Remission from Alcohol Dependence.

OBJECTIVE: The present study examined how effort to regulate alcohol use may interact with anxiety and affective disorders to influence long-term remission from alcohol dependence. METHOD: Using participants (n= 96; 73% male; 66% children of alcoholics; 71% non-Hispanic Caucasian; 26% Hispanic) from a high-risk community study who showed evidence of recovered alcohol dependence at baseline, the present study examined whether effort to regulate alcohol use at the baseline assessment significantly influenced the likelihood of maintaining remission from alcohol dependence at the 10 year follow-up. This study also examined whether having an anxiety or affective disorder interacted with effort to regulate alcohol use. All analyses controlled for treatment history, baseline alcohol use, parent alcoholism, age, and gender. RESULTS: Results from logistic regressions showed that effort to regulate alcohol use had a significant unique main effect on maintenance of remission from alcohol dependence. Having an affective and/or anxiety disorder did not have a significant main effect on the maintenance of remission. However, having an anxiety/affective disorder significantly moderated the influence of effort to regulate alcohol use such that the protective effect of effort to regulate use on remission from alcohol dependence was only significant for those without an affective or anxiety disorder. CONCLUSIONS: Individuals who try harder to limit their drinking are more likely to maintain long-term remission from alcohol dependence. However, affective and anxiety disorders may undermine the protective effect of effort to regulate alcohol use on long-term remission.