Genetic Susceptibility and Childhood Adversity: Gene-Environment Interaction in Attention-Deficit/Hyperactivity Disorder

Abstract Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly heritable neurodevelopmental disorder influenced by complex gene-environment interactions. Although interest in such interactions has increased in recent years, previous studies have been conducted in case-control or population-based settings. In the present study, we performed a case-only design to assess interactions between polygenic scores for ADHD (PGSADHD) and perinatal and childhood stressful life events, in a clinical sample of 852 adults with ADHD. Significant interactions between the genetic liability of ADHD and childhood stressful life events were identified. Specifically, the effect of the PGSADHD on the disorder was stronger among individuals who were exposed to emotional abuse, family violence, or extreme family stress in childhood compared to those who had not been exposed (OR = 1.31; 95% CI = 1.13–1.52; P = 3E-4). These results were robust when accounting for potential gene-environment correlation between the genetic liability of ADHD and childhood maltreatment. Also, individuals with ADHD exposed to at least one of these adverse events exhibited greater ADHD symptom severity, increased functional impairment, diminished sustained attention, and more depressive symptoms. These results suggest that early adverse experiences may exacerbate the effects of genetic predisposition, and amplify the clinical expression of ADHD. Our findings highlight the importance of considering gene-environment interactions to understand the heterogeneity of ADHD and the potential of the case-only design to detect this type of interaction.