ADHD, epilepsy, and related childhood psychopathology : understanding shared genetic risk, developmental trajectories, and pharmacological treatment safety

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder, affecting 5-7% of children and 2.5-5% of adults worldwide. The disorder is characterized by excessive and age-inappropriate symptoms of inattention, hyperactivity, and impulsivity, which impair everyday functioning across several settings (home, school, work). Although great advances have been made in ADHD research during the past decades, many questions remain regarding the causes and consequences of ADHD. ADHD is conceptualized as an early onset disorder, underpinned by varying degrees of neurological delay or dysfunction that may be exacerbated by environmental factors. The disorder is developmentally complex, and extensive comorbidity with other psychiatric and non-psychiatric disorders is the rule rather than the exception. In this thesis, quantitative and molecular genetic research designs were used to explore important and poorly understood questions regarding development, treatment safety, and comorbidity in ADHD, epilepsy and related childhood psychopathology.

In Study 1, we addressed the question of whether perceived immaturity is related to the developmental course of ADHD from childhood to early adulthood. Using data from a longitudinal twin study, we estimated the overlap between ADHD and immaturity from ages 8-9 to 19-20 years. Results showed that immaturity plays a small but significant role in ADHD in childhood and adolescence, largely due to shared genetic factors that diminish in importance with age. We also showed evidence for ADHD-related genetic stability across ages, and genetic innovation during adolescence and early adulthood. These findings may partly explain why some children show a decrease in ADHD symptoms from childhood to early adulthood, whereas others show a more persistent, chronic, disorder expression.

In Study 2, we explore whether common genetic risk variants associated with ADHD also influences a broad range of related childhood psychopathology. Results suggested that genetic risk for ADHD, summed to a polygenic risk score (PRS), is associated with higher levels of neurodevelopmental, externalizing, and to a lesser extent, internalizing problems. Importantly, these associations could largely be attributed to a general psychopathology factor, capturing covariance across symptoms dimensions. These findings provide evidence for wide-spread genetic pleiotropy across psychiatric conditions, and support the notion that many identified genetic risk variants associated with ADHD are likely to non-specifically increase liability towards broad childhood psychiatric problems.

In Study 3, we broaden our focus beyond psychiatric conditions to address the overlap between ADHD and epilepsy using a family co-aggregation design. Results from this large, population based cohort suggest that ADHD and epilepsy commonly co-occur and that this risk increase extends to family members of epilepsy patients. Quantitative genetic analyses revealed only a moderate genetic overlap across the disorder. These findings suggest that, although highly comorbid, epilepsy may be less genetically related to ADHD as compared to traditional neurodevelopmental disorders.

In Study 4, we address the safety of ADHD pharmacological treatment in patients with a history of epileptic seizures. Using a within-individual comparison design to adjust for time-constant confounders that vary between individuals (e.g. baseline disorder severity, shared genetic liability), we found that ADHD medications were not associated with an increased risk ofacute epileptic seizures. Despite long-standing concerns regarding the safety of stimulant ADHD medications in epilepsy patients, these findings suggest that ADHD medication treatment may be a safe and viable option even in patients with a seizure history.

The main findings from this thesis suggest that ADHD is related to both later maturation and a wide range of comorbid psychiatric conditions, partly due to shared genetic risk factors. Importantly, the shared genetic liability between ADHD and related psychiatric conditions appears to be in part attributable to a general liability towards broad childhood psychopathology. In contrast, epilepsy and ADHD comorbidity seems to be less influenced by shared genetic factors and more strongly influenced by environmental factors not shared by family members. ADHD medication does however not appear to be a risk factor for acute epileptic seizures among individuals with a seizure history. Taken together, results from this thesis highlight important aspects of development and comorbidity in ADHD, and lends support to the hypothesis ADHD may be considered part of broader continuum of psychopathology that is underpinned by partly shared genetic factors. Based on evidence thus far, this genetic shared liability appears less strongly related to epilepsy.