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

Joanna Martin,Qi Chen,Yi Lu,Benjamin B Lahey,Ralf Kuja-Halkola,Isabell Brikell,Robert Karlsson,Henrik Larsson,Erik Pettersson,Paul Lichtenstein

doi:10.1038/s41380-018-0109-2

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.

Highlights

IntroductionSignificant single nucleotide polymorphisms (SNPs)-heritability has been reported by the largest genome-wide association study (GWAS) of attention-deficit/hyperactivity disorder (ADHD) symptoms in population-based samples (5%(SE = 0.06) to 34% (SE = 0.17)) [9], with a near-complete sharing of genetic risks reported across these different ADHD definitions (rg = 0.94(SE = 0.20)) [8]
Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Department, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia 4 Department of Public Health Sciences, University of Chicago, Chicago, IL, USA 5 MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UKAttention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that affects 5–10% of children and is characterized by excessive inattentive, hyperactive, and impulsive symptoms [1]
The largest genome-wide association study (GWAS) of clinical attention-deficit/hyperactivity disorder (ADHD) to date identified the first genome-wide significant loci associated with ADHD, and estimated the proportion of phenotypic variance explained by measured single nucleotide polymorphisms (SNPs) at 22% (standard error (SE) = 0.01) [8]

Summary

Introduction

Significant SNP-heritability has been reported by the largest GWAS of ADHD symptoms in population-based samples (5%(SE = 0.06) to 34% (SE = 0.17)) [9], with a near-complete sharing of genetic risks reported across these different ADHD definitions (rg = 0.94(SE = 0.20)) [8]. Findings from population-based twin studies have reported moderate to strong genetic correlations between ADHD and other childhood psychiatric conditions, including autistic traits (rg range 0.54–87) [11], learning disabilities (rg range 0.31–41) [12,13,14], oppositional defiant and conduct problems (rg range 0.46–74) [15,16,17], anxiety (rg range 0.45–58), and depression (rg range 0.34–77) [11]. Mixed findings have been reported for ADHD PRS and associations with autism and depression [23,24,25,26,27,28]

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