Polygenic Risk Score for Smoking is associated with Externalizing Psychopathology and Disinhibited Personality Traits but not Internalizing Psychopathology in Adolescence

Abstract

ImportanceLarge consortia of genome wide association studies have yielded more accurate polygenic risk scores (PRS) that aggregate the small effects of many genetic variants to characterize the genetic architecture of disorders and provide a personalized measure of genetic risk.ObjectiveWe examined whether a PRS for smoking measured genetic risk for general behavioral disinhibition by estimating its associations with externalizing and internalizing psychopathology and related personality traits. We examined these associations at multiple time points in adolescence using more refined phenotypes defined by stable characteristics across time and at young ages, which reduced potential confounds associated with cumulative exposure to substances and reverse causality.MethodsRandom intercept panel models were fit to symptoms of conduct disorder, oppositional defiant disorder, major depressive disorder (MDD), and teacher ratings of externalizing and internalizing problems and personality traits at ages 11, 14, and 17 years-old in the Minnesota Twin Family Study (N = 3225).ResultsThe smoking PRS had strong associations with the random intercept factors for all the externalizing measures (mean standardized β = .27), agreeableness (β=−.22, 95% CI: −.28, −.16), and conscientiousness (β=−.19, 95% CI: −.24, −.13), but was not significantly associated with the internalizing measures (mean β = .06) or extraversion (β=.01, 95% CI: −.05, .07). After controlling for smoking at age 17, the associations with the externalizing measures (mean β = .13) and personality traits related to behavioral control (mean β = −.10) remained statistically significant.Conclusions and RelevanceThe smoking PRS measures genetic influences that contribute to a spectrum of phenotypes related to behavioral disinhibition including externalizing psychopathology and normal-range personality traits related to behavioral control, but not internalizing psychopathology. Continuing to identify the correlates and delineate the mechanisms of the genetic influences associated with disinhibition could have substantial impact in mitigating a variety of public health problems (e.g., mental health, academic achievement, criminality).Key PointsQuestionDoes a polygenic risk scores (PRS) for smoking measure genetic risk for behavioral disinhibition in general?FindingsThe smoking PRS was associated with externalizing psychopathology and personality traits related to behavioral control, but not internalizing psychopathology and extraversion during adolescence, even after controlling for smoking status.MeaningThe smoking PRS measures genetic influences on behavioral disinhibition in general which is associated with a variety of important outcomes including mental health, academic success, and criminality.

Maternal and child genetic liability for smoking and caffeine consumption and child mental health: an intergenerational genetic risk score analysis in the ALSPAC cohort

“…Even though this requires further testing, it could provide some initial evidence that the association between the maternal smoking GRS and offspring externalising problems is more likely to be pleiotropic than confounded by maternal depression. Further, other studies suggest that the genetic instrument for smoking initiation may not only measure smoking behaviour but also capture novelty‐seeking and impulsive behaviours even when only using genome‐wide significant SNPs [ 41 , 45 , 46 , 47 ]. In addition, GSCAN summary statistics for smoking initiation showed a strong genetic correlation with ADHD and risk tolerance behaviour, which could make pleiotropic effects more likely [ 25 ].…”

Maternal and child genetic liability for smoking and caffeine consumption and child mental health: An intergenerational genetic risk score analysis in the ALSPAC cohort

“…ADHD/conduct disorder in childhood with extraversion & anger personality traits in mothers outside of pregnancy). Third, many mental health phenotypes in childhood were based on maternal report, which may not accurately reflect offspring’s mental health problems (48,49) but rather mothers own mental health status (50,51). Fourth, we constructed PRS for smoking initiation based on the latest GWAS that included ALSPAC mothers (26).…”

“…Even though this requires further testing, it could provide some initial evidence that the association between the maternal smoking GRS and offspring externalising problems is more likely to be pleiotropic than confounded by maternal depression. Further, other studies suggest that the genetic instrument for smoking initiation may not only measure smoking behaviour but also capture novelty-seeking and impulsive behaviours even when only using genome-wide significant SNPs (41,45–47). In addition, GSCAN summary statistics for smoking initiation showed a strong genetic correlation with ADHD and risk tolerance behaviour, which could make pleiotropic effects more likely (25).…”

Alcohol and nicotine polygenic scores are associated with the development of alcohol and nicotine use problems from adolescence to young adulthood

“…Using the same sample as in this report, we have also shown that these non‐specific effects extend beyond substance use to include externalizing problems (rule‐breaking and aggression) from ages 11 to 17 years (i.e. prior to peak substance use), even after adjusting for contemporaneous nicotine use [40]. The notion of common genetic influences across substances is also consistent with multivariate twin studies that posited a common genetic etiology to account for the co‐occurrence and family transmission of substance use problems, antisocial behavior and disinhibited personality traits [41–43].…”