Associations of polygenic risk scores for smoking heaviness and lifetime cannabis use with tobacco and cannabis co-use trajectories among African Americans.

BACKGROUND: We aimed to identify distinct trajectories of tobacco, cannabis, and their co-use among African Americans, and to investigate whether these patterns were associated with polygenic risk scores (PRS) for tobacco and cannabis use. METHOD: Participants (N=428 participants; 50.9% male) were initially recruited for an elementary school-based prevention in a Mid-Atlantic city when they were in first grade. From ages 14-26, participants reported on their frequency of tobacco and cannabis use in the past year during annual assessments. DNA was collected from participants at age 21. PRS for smoking heaviness (i.e., cigarettes per day) and lifetime cannabis use were created based on genome-wide association study results derived from Liu et al. (2019) and Pasman et al. (2018), respectively. RESULTS: We identified five distinct trajectories of tobacco and cannabis co-use, including (1) Low Tobacco and Cannabis Use, (2) Adolescent Limited Tobacco and Cannabis Use, (3) Experimental Cannabis, Young Adult Increasing Tobacco, (4) Experimental Tobacco, Young Adult Increasing Cannabis, and (5) High, Chronic Tobacco and Cannabis Use. Compared to the Low Tobacco and Cannabis Use subgroup, individuals in the High, Chronic Tobacco and Cannabis Use subgroup had greater PRS for smoking heaviness, and individuals in the Experimental Cannabis, Young Adult Increasing Tobacco subgroup had higher PRS for lifetime cannabis use. CONCLUSIONS: Polygenic risk for lifetime cannabis use and smoking heaviness is associated with the developmental progression of tobacco and cannabis co-use among African Americans, furthering knowledge on the etiology of co-use in this population.

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.

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.

Alcohol use disorder, psychiatric comorbidities, marriage and divorce in a high-risk sample.

OBJECTIVE: To examine associations between alcohol use disorder (AUD), its psychiatric comorbidities, and their interactions, with marital outcomes in a diverse high-risk, genetically informative sample. METHOD: Participants included European ancestry (EA; n = 4,045) and African ancestry (AA; n = 1,550) individuals from the multigenerational Collaborative Study on the Genetics of Alcoholism (COGA) sample (56% female, Mage ∼ 41 years). Outcomes were lifetime marriage and divorce. Predictors included lifetime AUD, an alcohol problems polygenic score (PRS), and AUD comorbidities, including conduct or antisocial personality disorder (ASP), cannabis dependence/abuse (CAN), frequent tobacco use (TOB), and major depressive disorder (MDD). Mixed effect Cox models and generalized linear mixed effects models were fit. RESULTS: Among EA participants, those with AUD and CAN were less likely to marry (hazard ratios [HRs] 0.70-0.83, ps < 0.01). Among AA participants, those with AUD and TOB were less likely to marry (HRs 0.66-0.82, ps < 0.05) and those with MDD were more likely to marry (HR = 1.34, ps < 0.01). Among EA participants, AUD, CAN, TOB, and MDD were associated with higher odds of divorce (odds ratios [ORs] 1.59-2.21, ps < 0.01). Among AA participants, no predictors were significantly associated with divorce. Significant random effects indicated genetic and environmental influences on marriage, but only environmental factors on divorce. CONCLUSIONS: In a high-risk sample, AUD was associated with reduced likelihood of marriage in EA and AA individuals and increased risk of divorce in EA individuals. These associations were largely independent of comorbidities. Genetic and environmental background factors contributed to marriage, while only environmental background factors contributed to divorce. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Sibling comparisons elucidate the associations between educational attainment polygenic scores and alcohol, nicotine and cannabis.

BACKGROUND AND AIMS: The associations between low educational attainment and substance use disorders (SUDs) may be related to a common genetic vulnerability. We aimed to elucidate the associations between polygenic scores for educational attainment and clinical criterion counts for three SUDs (alcohol, nicotine and cannabis). DESIGN: Polygenic association and sibling comparison methods. The latter strengthens inferences in observational research by controlling for confounding factors that differ between families. SETTING: Six sites in the United States. PARTICIPANTS: European ancestry participants aged 25 years and older from the Collaborative Study on the Genetics of Alcoholism (COGA). Polygenic association analyses included 5582 (54% female) participants. Sibling comparisons included 3098 (52% female) participants from 1226 sibling groups nested within the overall sample. MEASUREMENTS: Outcomes included criterion counts for DSM-5 alcohol use disorder (AUDSX), Fagerström nicotine dependence (NDSX) and DSM-5 cannabis use disorder (CUDSX). We derived polygenic scores for educational attainment (EduYears-GPS) using summary statistics from a large (> 1 million) genome-wide association study of educational attainment. FINDINGS: In polygenic association analyses, higher EduYears-GPS predicted lower AUDSX, NDSX and CUDSX [P < 0.01, effect sizes (R2 ) ranging from 0.30 to 1.84%]. These effects were robust in sibling comparisons, where sibling differences in EduYears-GPS predicted all three SUDs (P < 0.05, R2 0.13-0.20%). CONCLUSIONS: Individuals who carry more alleles associated with educational attainment tend to meet fewer clinical criteria for alcohol, nicotine and cannabis use disorders, and these effects are robust to rigorous controls for potentially confounding factors that differ between families (e.g. socio-economic status, urban-rural residency and parental education).

The Role of Individual and Contextual Factors in Differentiating Substance Use Profiles among Adolescents.

BACKGROUND: Adolescent substance use is a significant public health concern due to its prevalence and associated negative consequences. Although many adolescents use substances, there is substantial heterogeneity in their use patterns. Identifying risk and protective factors that differentiate adolescents with different substance use profiles is important for preventing negative consequences for those at risk. OBJECTIVE: This study identified distinct latent profiles of substance use by considering adolescents' involvement in multiple common and illicit substances as well as related problems and examined the extent to which individual and contextual factors in the family, peer, school, and neighborhood environments were related to adolescents' membership of substance use profiles. METHOD: Data came from 9,155 high school students (51% female; 74% European American) who completed electronic surveys in the 2009 Dane County Youth Assessment (DCYA). Latent class analysis (LCA) was conducted to identify profiles of adolescent substance involvement and related problems. Multinomial logistic regression was conducted to examine associations between individual and contextual factors and latent class membership. RESULTS: LCA identified four distinct profiles of adolescent substance use characterized by both licit and illicit substance use and related problems: Abstainers (56.3%), Alcohol-only users (25.6%), Alcohol-cigarette-marijuana users (13.8%), and Problem polysubstance users (4.3%). Controlling for demographics, individual and contextual factors were associated with adolescents' likelihoods of membership in substance use profiles; notably, the associations varied to some extent across substance use profiles. CONCLUSIONS: Substance use is heterogeneous among adolescents. Effects of risk and protective factors on substance use vary depending on adolescents' substance use patterns.

Associations of parental alcohol use disorders and parental separation with offspring initiation of alcohol, cigarette and cannabis use and sexual debut in high-risk families.

BACKGROUND AND AIMS: Parental alcohol use disorders (AUDs) and parental separation are associated with increased risk for early use of alcohol in offspring, but whether they increase risks for early use of other substances and for early sexual debut is under-studied. We focused on associations of parental AUDs and parental separation with substance initiation and sexual debut to (1) test the strength of the associations of parental AUDs and parental separation with time to initiation (age in years) of alcohol, tobacco and cannabis use and sexual debut and (2) compare the strength of association of parental AUD and parental separation with initiation. DESIGN: Prospective adolescent and young adult cohort of a high-risk family study, the Collaborative Study on the Genetics of Alcoholism (COGA). SETTING: Six sites in the United States. PARTICIPANTS: A total of 3257 offspring (aged 14-33 years) first assessed in 2004 and sought for interview approximately every 2 years thereafter; 1945 (59.7%) offspring had a parent with an AUD. MEASUREMENTS: Diagnostic interview data on offspring substance use and sexual debut were based on first report of these experiences. Parental life-time AUD was based on their own self-report when parents were interviewed (1991-2005) for most parents, or on offspring and other family member reports for parents who were not interviewed. Parental separation was based on offspring reports of not living with both biological parents most of the time between ages 12 and 17 years. FINDINGS: Parental AUDs were associated with increased hazards for all outcomes, with cumulative hazards ranging from 1.19 to 2.71. Parental separation was also an independent and consistent predictor of early substance use and sexual debut, with hazards ranging from 1.19 to 2.34. The strength of association of parental separation with substance initiation was equal to that of having two AUD-affected parents, and its association with sexual debut was stronger than the association of parental AUD in one or both parents. CONCLUSIONS: Parental alcohol use disorders (AUDs) and parental separation are independent and consistent predictors of increased risk for early alcohol, tobacco and cannabis use and sexual debut in offspring from families with a high risk of parental AUDs.