The contribution of common genetic risk variants for ADHD to a general factor of childhood psychopathology

Abstract

Common genetic risk variants have been implicated in the etiology of clinical attention-deficit/hyperactivity disorder (ADHD) diagnoses and symptoms in the general population. However, given the extensive comorbidity across ADHD and other psychiatric conditions, the extent to which genetic variants associated with ADHD also influence broader psychopathology dimensions remains unclear. The aim of this study was to evaluate the associations between ADHD polygenic risk scores (PRS) and a broad range of childhood psychiatric symptoms, and to quantify the extent to which such associations can be attributed to a general factor of childhood psychopathology. We derived ADHD PRS for 13,457 children aged 9 or 12 from the Child and Adolescent Twin Study in Sweden, using results from an independent meta-analysis of genome-wide association studies of ADHD diagnosis and symptoms. We estimated associations between ADHD PRS, a general psychopathology factor, and several dimensions of neurodevelopmental, externalizing, and internalizing symptoms, using structural equation modeling. Higher ADHD PRS were statistically significantly associated with elevated neurodevelopmental, externalizing, and depressive symptoms (R² = 0.26-1.69%), but not with anxiety. After accounting for a general psychopathology factor, on which all symptoms loaded positively (mean loading = 0.50, range = 0.09-0.91), an association with specific hyperactivity/impulsivity remained significant. ADHD PRS explained ~ 1% (p value < 0.0001) of the variance in the general psychopathology factor and ~ 0.50% (p value < 0.0001) in specific hyperactivity/impulsivity. Our results suggest that common genetic risk variants associated with ADHD, and captured by PRS, also influence a general genetic liability towards broad childhood psychopathology in the general population, in addition to a specific association with hyperactivity/impulsivity symptoms.

Fig. 1

Path diagram of the general factor model in the A-TAC subsample A and the SMFQ/SCARED subsample B. Path diagram for the general factor models, presented by study subsample. Latent factors are depicted as circles. For clarity, covariates (age, sex and the six principal components) and correlations across latent trait factors are omitted in the above graphical representation. The models consisted of a latent general psychopathology factor (GP) and specific latent trait factors reflecting symptoms dimensions of inattention (IA), hyperactivity/impulsivity (H/I), autism spectrum disorder (ASD), learning difficulties (LD), oppositional defiant disorder (ODD), conduct disorder (CD), depression (DEP), and anxiety (ANX) or panic disorder (PD), generalized anxiety (GAD), separation anxiety (SAD), school anxiety (SA), and social phobia (SP). Variances for all latent factors were fixed at 1. Measured variables are depicted as squares, and include the ADHD PRS and all symptoms items from the Autism-Tics, ADHD, and Other Comorbidities inventory (A-TAC), the Short Mood and Feelings Questionnaire (SMFQ), and the Screen for Child Anxiety Related Emotional Disorders (SCARED). Numbers 1…X indicate the number of symptom items loading onto each specific latent trait factor. β₁–β_x represent the regression coefficients, regressing each latent variable onto ADHD PRS. Note that the corresponding path diagrams for the correlated factors models are identical, excluding the general psychopathology factor