A Developmentally-Informative Genome-wide Association Study of Alcohol Use Frequency.

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

Genetic nurture effects for alcohol use disorder.

We tested whether aspects of the childhood/adolescent home environment mediate genetic risk for alcohol problems within families across generations. Parental relationship discord and parental divorce were the focal environments examined. The sample included participants of European ancestry (N = 4806, 51% female) and African ancestry (N = 1960, 52% female) from the high-risk Collaborative Study on the Genetics of Alcoholism. Alcohol outcomes in the child generation included lifetime criterion counts for DSM-5 Alcohol Use Disorder (AUD), lifetime maximum drinks in 24 h, age at initiation of regular drinking, and age at first alcohol intoxication. Predictors in the parent generation included relationship discord, divorce, alcohol measures parallel to those in the child generation, and polygenic scores for alcohol problems. Parental polygenic scores were partitioned into alleles that were transmitted and non-transmitted to the child. The results from structural equation models were consistent with genetic nurture effects in European ancestry families. Exposure to parental relationship discord and parental divorce mediated, in part, the transmission of genetic risk for alcohol problems from parents to children to predict earlier ages regular drinking (ßindirect = -0.018 [-0.026, -0.011]) and intoxication (ßindirect = -0.015 [-0.023, -0.008]), greater lifetime maximum drinks (ßindirect = 0.006 [0.002, 0.01]) and more lifetime AUD criteria (ßindirect = 0.011 [0.006, 0.016]). In contrast, there was no evidence that parental alleles had indirect effects on offspring alcohol outcomes via parental relationship discord or divorce in the smaller number of families of African ancestry. In conclusion, parents transmit genetic risk for alcohol problems to their children not only directly, but also indirectly via genetically influenced aspects of the home environment. Further investigation of genetic nurture in non-European samples is needed.

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.

Alcohol use polygenic risk score, social support, and alcohol use among European American and African American adults.

Alcohol use is influenced by genetic and environmental factors. We examined the interactive effects between genome-wide polygenic risk scores for alcohol use (alc-PRS) and social support in relation to alcohol use among European American (EA) and African American (AA) adults across sex and developmental stages (emerging adulthood, young adulthood, and middle adulthood). Data were drawn from 4,011 EA and 1,274 AA adults from the Collaborative Study on the Genetics of Alcoholism who were between ages 18-65 and had ever used alcohol. Participants completed the Semi-Structured Assessment for the Genetics of Alcoholism and provided saliva or blood samples for genotyping. Results indicated that social support from friends, but not family, moderated the association between alc-PRS and alcohol use among EAs and AAs (only in middle adulthood for AAs); alc-PRS was associated with higher levels of alcohol use when friend support was low, but not when friend support was high. Associations were similar across sex but differed across developmental stages. Findings support the important role of social support from friends in buffering genetic risk for alcohol use among EA and AA adults and highlight the need to consider developmental changes in the role of social support in relation to alcohol use.

COVID-19 Related Stressors, Parent-Child Relationship, and Alcohol Use and Mental Health Profiles Among White and Hispanic/Latinx First-Year College Students.

Transitioning to college during the novel coronavirus disease 2019 (COVID-19) pandemic may increase risk for alcohol use and mental health problems. We examined how COVID-19 related stressors and parent-child relationships are independently and interactively associated with alcohol use and mental health profiles in a sample of first-year college students (N = 425, 34.8% Hispanic/Latinx; 74.9% female) who completed an online survey in October 2020. Latent profile analysis identified four profiles: well-adjusted (53.2%), mental health problems only (21.6%), alcohol use only (17.4%), and comorbid (7.8%). COVID-19 related stressful events increased risk of being in the alcohol use only and comorbid profiles, whereas COVID-19 related worries increased risk of being in the mental health problems only profile. Parent-child relationship quality lowered risk of being in the mental health problems only and the comorbid profiles. In addition, parent-child relationship quality moderated the role of COVID-19 related worries such that COVID-19 related worries were associated with lower odds of being in the comorbid profile when parent-child relationship quality was high but not when parent-child relationship quality was low. Strengthening parent-child relationship quality appears important for promoting college students' well-being.

The impact of receiving polygenic risk scores for alcohol use disorder on psychological distress, risk perception, and intentions to reduce drinking.

For the return of polygenic risk scores to become an acceptable clinical practice in psychiatry, receipt of polygenic risk scores must be associated with minimal harm and changes in behavior that decrease one's risk for developing a psychiatric outcome. Data from a randomized controlled trial was used to assess the impact of different levels of hypothetical polygenic risk scores for alcohol use disorder on psychological distress, risk perception, and intentions to change drinking behaviors. The analytic sample consisted of 325 participants recruited from an urban, public university. Results demonstrated that there were significant increases in psychological distress as the level of genetic risk for alcohol use disorder increased. In addition, the perceived chance of developing alcohol use disorder significantly increased as the level of genetic risk increased. Promisingly, a greater proportion of participants indicated that they would intend to engage in follow-up behaviors, such as seeking additional information, talking to a healthcare provider about risk, and reducing drinking behaviors, as the level of genetic risk increased. Returning polygenic risk scores for alcohol use disorder in a clinical setting has the potential to promote risk-reducing behavior change, especially with increasing levels of genetic risk. The study was registered on ClinicalTrials.gov (Identifier: NCT05143073).

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.

The role of adolescent social relationships in promoting alcohol resistance: Interrupting the intergenerational transmission of alcohol misuse.

Genetic factors contribute to the intergenerational transmission of alcohol misuse, but not all individuals at high genetic risk develop problems. The present study examined adolescent relationships with parents, peers, and romantic partners as predictors of realized resistance, defined as high biological risk for disorder combined with a healthy outcome, to alcohol initiation, heavy episodic drinking, and alcohol use disorder (AUD). Data were from the Collaborative Study on the Genetics of Alcoholism (N = 1,858; 49.9% female; mean age at baseline = 13.91 years). Genetic risk, indexed using family history density and polygenic risk scores for alcohol problems and AUD, was used to define alcohol resistance. Adolescent predictors included parent-child relationship quality, parental monitoring, peer drinking, romantic partner drinking, and social competence. There was little support for the hypothesis that social relationship factors would promote alcohol resistance, with the exception that higher father-child relationship quality was associated with higher resistance to alcohol initiation ( ß ^ = - 0.19 , 95% CI = -0.35, -0.03). Unexpectedly, social competence was associated with lower resistance to heavy episodic drinking ( ß ^ = 0.10 , 95% CI = 0.01, 0.20). This pattern of largely null effects underscores how little is known about resistance processes among those at high genetic risk for AUD.

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.

Racial Discrimination and Alcohol Problems: Examining Interactions with Genetic Risk and Impulsivity among African American Young Adults.

Experiences of racial discrimination have been shown to increase risk for alcohol problems. Some individuals may be particularly vulnerable to the negative effects of racial discrimination. However, little research has examined interaction effects between racial discrimination and individual characteristics, such as genetic predispositions and personality, in relation to alcohol outcomes. This study examined whether genetic risk and dimensions of impulsivity moderate the association between racial discrimination and alcohol problems among African American young adults (n = 383, Mage = 20.65, SD = 2.28; 81% female). Participants completed online surveys and provided a saliva sample for genotyping. Results from multiple regression analyses indicated that both blatant and subtle forms of racial discrimination (i.e., experience of racist events and racial microaggressions) were associated with more alcohol problems. Racial microaggressions interacted with dimensions of impulsivity in relation to alcohol problems, such that racial microaggressions were associated with more alcohol problems when negative urgency was high or when sensation seeking was low. There was no significant interaction between alcohol use disorder genome-wide polygenic score and experience of racist events or racial microaggression in relation to alcohol problems, which may partly reflect low power due in part to limited representation of African-Americans in genetic research. The findings highlight the need to increase the representation of African Americans in genetically-informed research in order to better characterize genetic risk and understand gene-environment interaction in this understudied population, as well as the importance of examining impulsivity as a multidimensional construct that interacts with racial discrimination in relation to alcohol outcomes.

Polygenic contributions to alcohol use and alcohol use disorders across population-based and clinically ascertained samples.

BACKGROUND: Studies suggest that alcohol consumption and alcohol use disorders have distinct genetic backgrounds. METHODS: We examined whether polygenic risk scores (PRS) for consumption and problem subscales of the Alcohol Use Disorders Identification Test (AUDIT-C, AUDIT-P) in the UK Biobank (UKB; N = 121 630) correlate with alcohol outcomes in four independent samples: an ascertained cohort, the Collaborative Study on the Genetics of Alcoholism (COGA; N = 6850), and population-based cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC; N = 5911), Generation Scotland (GS; N = 17 461), and an independent subset of UKB (N = 245 947). Regression models and survival analyses tested whether the PRS were associated with the alcohol-related outcomes. RESULTS: In COGA, AUDIT-P PRS was associated with alcohol dependence, AUD symptom count, maximum drinks (R2 = 0.47-0.68%, p = 2.0 × 10-8-1.0 × 10-10), and increased likelihood of onset of alcohol dependence (hazard ratio = 1.15, p = 4.7 × 10-8); AUDIT-C PRS was not an independent predictor of any phenotype. In ALSPAC, the AUDIT-C PRS was associated with alcohol dependence (R2 = 0.96%, p = 4.8 × 10-6). In GS, AUDIT-C PRS was a better predictor of weekly alcohol use (R2 = 0.27%, p = 5.5 × 10-11), while AUDIT-P PRS was more associated with problem drinking (R2 = 0.40%, p = 9.0 × 10-7). Lastly, AUDIT-P PRS was associated with ICD-based alcohol-related disorders in the UKB subset (R2 = 0.18%, p < 2.0 × 10-16). CONCLUSIONS: AUDIT-P PRS was associated with a range of alcohol-related phenotypes across population-based and ascertained cohorts, while AUDIT-C PRS showed less utility in the ascertained cohort. We show that AUDIT-P is genetically correlated with both use and misuse and demonstrate the influence of ascertainment schemes on PRS analyses.

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.

A systematic review of gene-by-intervention studies of alcohol and other substance use.

Alcohol and other substance use problems are common, and the efficacy of current prevention and intervention programs is limited. Genetics may contribute to differential effectiveness of psychosocial prevention and intervention programs. This paper reviews gene-by-intervention (G×I) studies of alcohol and other substance use, and implications for integrating genetics into prevention science. Systematic review yielded 17 studies for inclusion. Most studies focused on youth substance prevention, alcohol was the most common outcome, and measures of genotype were heterogeneous. All studies reported at least one significant G×I interaction. We discuss these findings in the context of the history and current state of genetics, and provide recommendations for future G×I research. These include the integration of genome-wide polygenic scores into prevention studies, broad outcome measurement, recruitment of underrepresented populations, testing mediators of G×I effects, and addressing ethical implications. Integrating genetic research into prevention science, and training researchers to work fluidly across these fields, will enhance our ability to determine the best intervention for each individual across development. With growing public interest in obtaining personalized genetic information, we anticipate that the integration of genetics and prevention science will become increasingly important as we move into the era of precision medicine.

Genetic propensity for risky behavior and depression and risk of lifetime suicide attempt among urban African Americans in adolescence and young adulthood.

Suicide attempts (SA) among African Americans have increased at a greater rate than any other racial/ethnic group. Research in European ancestry populations has indicated that SA are genetically influenced; however, less is known about the genetic contributors that underpin SA among African Americans. We examined whether genetic propensity for depression and risky behaviors (assessed via polygenic risk scores; PRS) independently and jointly are associated with SA among urban, African Americans and whether sex differences exist in these relations. Participants (N = 1,157, 45.0% male) were originally recruited as part of two first grade universal school-based prevention trials. Participants reported in adolescence and young adulthood on whether they ever attempted suicide in their life. Depression and risky behaviors PRS were created based on large-scale genome-wide association studies conducted by Howard et al. (2019) and Karlson Línner et al. (2019), respectively. There was a significant interaction between the risky behavior PRS and depression PRS such that the combination of high risky behavior polygenic risk and low/moderate polygenic risk for depression was associated with greater risk for lifetime SA among the whole sample and African American males specifically. In addition, the risky behavior PRS was significantly positively associated with lifetime SA among African American males. These findings provide preliminary evidence regarding the importance of examining risky behavior and depression polygenic risk in relation to SA among African Americans, though replication of our findings in other African American samples is needed.

Pathways Between a Polygenic Score for Educational Attainment and Higher Educational Attainment in an African American Sample.

We investigated the extent to which performance on standardized achievement tests, executive function (EF), and aggression in childhood and adolescence accounted for the relationship between a polygenic score for educational attainment (EA PGS) and years of education in a community sample of African Americans. Participants (N = 402; 49.9% female) were initially recruited for an elementary school-based prevention trial in a Mid-Atlantic city and followed into adulthood. In first and twelfth grade, participants completed math and reading standardized tests and teachers reported on participants' aggression and EF, specifically impulsivity and concentration problems. At age 20, participants reported on their years of education and post-secondary degrees attained and their genotype was assayed from blood or buccal swabs. An EA PGS was created using results from a large-scale GWAS on EA. A higher EA PGS was associated with higher education indirectly via adolescent achievement. No other mediating mechanisms were significant. Adolescent academic achievement is thus one mechanism through which polygenic propensity for EA influences post-secondary education among urban, African American youth.

Racial discrimination and alcohol problems among African American young adults: Examining the moderating effects of racial socialization by parents and friends.

OBJECTIVE: Racial discrimination is a stressor that may put African Americans at risk for alcohol use and related problems. We examined whether experiences of blatant (racist events) and subtle (racial microaggressions) forms of racial discrimination were associated with alcohol consumption and alcohol problems among African American young adults, and whether childhood/adolescence racial socialization by parents and friends moderated these associations. METHOD: The sample included 383 African American young adults (Mage = 20.65, SD = 2.28; 81% female) who completed an electronic survey in Fall, 2017. Hierarchical linear regression analyses were conducted in Mplus. RESULTS: Experiences of racist events and racial microaggressions were associated with higher levels of alcohol consumption and more alcohol problems. Racial socialization by friends, but not parents, moderated these associations. Specifically, cultural socialization by friends buffered the effect of racist events on alcohol consumption and alcohol problems, whereas promotion of mistrust by friends exacerbated the effect of racial microaggressions on alcohol problems. CONCLUSIONS: Both blatant and subtle forms of racial discrimination were associated with higher risk for alcohol use or problems among African American young adults. Racial socialization by friends while growing up may play an important role in alcohol use outcomes during young adulthood. Findings highlight the importance of considering different forms of racial discrimination and emphasize the unique roles of racial socialization across different social contexts (i.e., parent and peers or friends) in relation to psychosocial outcomes among African American individuals. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Genetic feedback for psychiatric conditions: Where are we now and where are we going.

Genome-wide association studies are rapidly advancing our understanding of the genetic architecture of complex disorders, including many psychiatric conditions such as major depression, schizophrenia, and substance use disorders. One common goal of genome-wide association studies is to use findings for enhanced clinical prediction in the future, which can aid in identifying at-risk individuals to enable more effective prevention screening and treatment strategies. In order to achieve this goal, we first need to gain a better understanding of the issues surrounding the return of complex genetic results. In this article, we summarize the current literature on: (a) genetic literacy in the general population, (b) the public's interest in receiving genetic test results for psychiatric conditions, (c) how individuals react to and interpret their genotypic information for specific psychiatric conditions, and (d) gaps in our knowledge that will be critical to address as we move toward returning genotypic information for psychiatric conditions in both research and clinical settings. By reviewing extant studies, we aim to increase awareness of the potential benefits and consequences of returning genotypic information for psychiatric conditions.

Latent trajectories of alcohol use from early adolescence to young adulthood: Interaction effects between 5-HTTLPR and parenting quality and gender differences.

Using a large and nationally representative sample, we examined how adolescents' 5-HTTLPR genotype and perceived parenting quality independently and interactively associated with trajectories of alcohol use from early adolescence to young adulthood and whether/how gender may moderate these associations. The sample for this study included 13,749 adolescents (53.3% female; 56.3% non-Hispanic White, 21.5% Black, 16.0% Hispanic, and 6.1% Asian) followed prospectively from adolescence to young adulthood. Using growth mixture modeling, we identified four distinct trajectories of alcohol use (i.e., persistent heavy alcohol use, developmentally limited alcohol use, late-onset heavy alcohol use, and non/light alcohol use). Results indicated that the short allele of 5-HTTLPR was associated with higher risk of membership in the persistent and the late-onset heavy alcohol use trajectories. Parenting quality was associated with lower likelihoods of following the persistent heavy and the developmentally limited alcohol use trajectories but was not associated with risk of membership for the late-onset heavy drinking trajectory. 5-HTTLPR interacted with parenting quality to predict membership in the persistent heavy alcohol use trajectory for males but not for females. Findings highlighted the importance of considering the heterogeneity in trajectories of alcohol use across development and gender in the study of Gene Environment interactions in alcohol use.

The Family Check-up Intervention Moderates Polygenic Influences on Long-Term Alcohol Outcomes: Results from a Randomized Intervention Trial.

Alcohol problems are influenced by both genetic and environmental factors. Evidence from twin models and measured gene-environment interaction studies has demonstrated that the importance of genetic influences changes as a function of the environment. Research has also shown that family-centered interventions may protect genetically susceptible youth from developing substance use problems. In this study, we brought large-scale gene identification findings into an intervention study to examine gene-by-intervention effects. Using genome-wide polygenic scores derived from an independent genome-wide association study of adult alcohol dependence, we examined whether an adolescent family-centered intervention would moderate the effect of genetic risk for alcohol dependence on lifetime alcohol dependence in young adulthood, approximately 15 years after the start of intervention, among European American (N = 271; 48.3% in the intervention condition) and African American individuals (N = 192; 51.6% in the intervention condition). We found that among European American individuals, the intervention moderated the association between alcohol dependence polygenic scores and lifetime alcohol dependence diagnosis in young adulthood. Among participants in the control condition, higher alcohol dependence polygenic scores were associated with a greater likelihood of receiving an alcohol dependence diagnosis; in contrast, among participants in the intervention condition, there was no association between alcohol dependence polygenic scores and alcohol dependence diagnosis. No moderation effect was found among African Americans. These results demonstrate that modifying environments of genetically vulnerable youth could reduce the likelihood of developing alcohol dependence and underscore the significance of environmentally focused prevention and intervention efforts.