Objective: To develop and validate clinically relevant polygenic scores (PGS) for alcohol (AUD), cannabis (CanUD), opioid (OUD), tobacco (TUD), and polysubstance use disorders (polySUD) across African (AA), European (EA), and Latinx (LA) ancestry populations. Methods: Using multiple genome-wide association study summary statistics and PGS methods, substance use disorder PGS were developed and evaluated in Indiana Biobank samples (IB, N: 1,356-24,989), then top-performing PGS were validated in All of Us Research Program samples (AOU, N: 62,389-209,952). Case and controls were defined using ICD-9/10 codes. All participants were aged 18 years or older (>=21 years for AUD controls). Clinical relevance was defined as an odds ratio (OR) >=2 for individuals with the highest PGS determined based on disorder prevalence compared to everyone else. Results: In EA and LA, all PGS achieved clinically relevant performance in both IB and AOU (ORs: 2.00-9.10; P <= 3.87E-4). In AA, PGS met this threshold in IB (ORs: 2.02-2.71; P <= 2.20E-4) but not in AOU (ORs: 1.28-1.56; P <=0.03). Overall, OUD PGS showed the strongest associations in most analyses, followed by CanUD and polySUD. Generally, compared to female PGS, male PGS had higher or comparable ORs, but the differences were not significant except AUD PGS in AOU LA. Conclusions: PGS demonstrated clinically meaningful risk prediction for substance use disorders in EA and LA, supporting the feasibility of future clinical implementation for population-level screening. However, reduced performance in AA underscores the urgent need for more genetic studies in that population.
D. Lai, M. Zhang, T.-H. Schwantes-An et al.· medRxiv· 0 citations
ABSTRACT Background The field's conventional understanding of how genetic factors impact risk for alcohol use disorder (AUD) typically focuses on direct genetic effects, or how an individual's own genetic predispositions are associated with the likelihood of experiencing clinically significant alcohol problems. More recently, studies of behavioral health outcomes in preclinical and human studies have demonstrated the potential importance of social genetic effects or the influence of a social partner's genotype on substance use and related outcomes. In this study, we sought to characterize social genetic effects for AUD, specifically in the context of marriage. Methods The sample included 660 opposite‐sex spousal dyads from the Collaborative Study on the Genetics of Alcoholism, restricted to individuals who were genetically similar to European reference panels. Measured and latent indicators of genetic risk included polygenic scores of problematic alcohol use (PGSPAU) and parental history of AUD (PHAUD), respectively. The outcome was Diaganostic and Statistical Manual (DSM)‐5 alcohol use disorder criterion count (AUDcrit) during marriage. Multilevel models accounted for the non‐independence of partners' data, including correlations between partners' genetic risk and residual covariance in AUDcrit. Results After accounting for direct genetic effects (i.e., the influence of one's own genetic predispositions) and the correlations between partners' genetic predispositions, we found that having a spouse with higher PGSPAU was associated with higher AUDcrit (B = 0.084, 95% CI [0.035, 0.132]). This social genetic effect was robust after adjusting for both partners' educational attainment. Spousal PHAUD was not associated with AUDcrit. Exploratory analyses indicated that the social genetic effect of spousal PGSPAU was stronger among male target individuals. Conclusions Findings highlight the potential importance of social genetic effects for understanding the pathways from genotype to alcohol use disorder and the need for further investigation of latent measures of genetic predispositions in studies of social genetic effects.
S. Kuo, V. McCutcheon, F. Aliev et al.· Alcohol, clinical & experime...· 0 citations
