European externalizing polygenic risk scores predicts adhd among mexican youth

Externalizing disorders are characterized by poor impulse control, such as rule-breaking behavior, aggression, impulsivity, and inattention. These disorders are relatively common in children and adolescents, with an estimated prevalence ranging from 2.1- 5.7%. Several studies have examined the association of externalizing PRS with externalizing symptoms in samples of European ancestry. However, less is known about the predictive ability of European ancestry externalizing PRS on phenotypic externalizing symptoms among Mexican youth. In the present study, we leveraged the largest GWAS to date on externalizing behaviors to examine whether externalizing PRS predicted a range of externalizing disorders diagnoses during adolescence, a sensitive developmental period during which genetic influences often peak. Participants (n= 1064 age range 12-17 years old; 58.8% female) were adolescents recruited for a general population survey on adolescent mental health who were genotyped. Externalizing disorders, specifically attention deficit hyperactivity disorder (ADHD), conduct disorder (CD), oppositional defiant disorder (ODD), and substance use disorder (SUD), were assessed via the computer-assisted World Mental Health Composite International Diagnostic Interview for adolescents. PRS were generated from the largest genome-wide association on externalizing symptoms that included over 1 million individuals of European ancestry. (Linner et al., 2021) Multivariate logistic regression models were conducted to determine the main effects of the externalizing PRS with ADHD, ODD, CD, SUD, or any externalizing disorder diagnosis. A greater externalizing PRS was associated with a greater odd of externalizing disorders (OR = 1.35 [1.14, 1.60]; p < 0.01, pseudoR2= 0.02), particularly ADHD (OR = 1.5 [1.2, 1.9]; p < 0.01, pseudoR2= 0.02). There were no main effects of the externalizing PRS in predicting any of the other externalizing disorders. Consistent with the positive associations of small effect sizes between the externalizing PRS and ADHD in populations of European descent (Linner et al., 2021), we found that higher externalizing PRS was associated with a greater odd of ADHD in Mexican adolescents and accounted for a very small amount of variance (pseudo R2 = 0.02). Positive associations of small effect size parallel previous work conducted in our sample examining the relationship between PRS for mental health phenotypes (e.g., depression, suicide ideation) derived from European ancestry samples and mental health outcomes in this cohort (Rabinowitz et al, 2020, Martínez-Levy et al., 2021). Greater externalizing genetic risk was associated with a greater odd of any externalizing disorder with a very small effect size observed (pseudo R2 = 0.02); nonetheless, we did not find an association between the externalizing PRS and the individual disorders of ODD, CD, and SUD. The lack of an association between the externalizing PRS and the other externalizing disorders (i.e., CD, ODD, or SUD) may be because environmental factors may better account for the development of these disorders in this cohort compared to genetic influences. (DuRietz et al., 2020) Our work demonstrates that the PRS generated on externalizing symptoms of individuals of European ancestry predicts externalizing disorders, particularly ADHD, in a diverse sample of Mexican adolescents, suggesting that the polygenic liability of these disorders is at least partially shared across populations.