Aging-Dependent Genetic Effects Associated to ADHD Predict Longitudinal Changes of Ventricular Volumes in Adulthood

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood-onset disorder that can persist into adult life. Most genetic studies have focused on investigating biological mechanisms of ADHD during childhood. However, little is known about whether genetic variants associated with ADHD influence structural brain changes throughout adulthood.

Methods: Participant of the study were drawn from a population-based sample of 3,220 healthy individuals drawn from the Rotterdam Study, with at least two magnetic resonance imaging (MRI)-scans (8,468 scans) obtained every 3-4 years. We investigate associations of genetic single nucleotide polymorphisms (SNPs) that have previously been identified in genome-wide association studies for ADHD, and trajectories of global and subcortical brain structures in an adult population (aged 50 years and older), acquired through MRI. We also evaluated the existence of age-dependent effects of these genetic variants on trajectories of brain structures. These analyses were reproduced among individuals 70 years of age or older to further explore aging-dependent mechanisms. We additionally tested baseline associations using the first MRI-scan of the 3,220 individuals.

Results: We observed significant age-dependent effects on the rs212178 in trajectories of ventricular size (lateral ventricles, P= 4E-05; inferior lateral ventricles, P=3.8E-03; third ventricle, P=2.5E-03; fourth ventricle, P=5.5E-03). Specifically, carriers of the G allele, which was reported as protective for ADHD, had a smaller increase of ventricular size compared with homozygotes for the A allele in elder stages. Post hoc analysis on the subset of individuals older than 70 years of age reinforced these results (lateral ventricles, P=7.3E-05). In addition, the rs4916723, and the rs281324 displayed nominal significant age-dependent effects in trajectories of the amygdala volume (P=1.4E-03), and caudate volume (P=1.8E-03), respectively.

Conclusions: To the best of our knowledge, this is the first study suggesting the involvement of protective genetic variants for ADHD on prevention of brain atrophy during adulthood.