Polygenic Risk Score–Derived Subcortical Connectivity Mediates Attention-Deficit/Hyperactivity Disorder Diagnosis

Background: Attention-deficit/hyperactivity disorder (ADHD) has substantial heritability, and a recent large-scale investigation has identified common genome-wide significant loci associated with increased risk for ADHD. Along the same lines, many studies using noninvasive neuroimaging have identified differences in brain functional connectivity in children with ADHD. We attempted to bridge these studies to identify differences in functional connectivity associated with common genetic risk for ADHD using polygenic risk score (PRS). Methods: We computed ADHD PRSs for all participants in our sample (N = 315, children 7–13 years of age, 196 with ADHD and 119 unaffected comparison children) using ADHD data from the Psychiatric Genomics Consortium as a discovery set. Magnetic resonance imaging was used to evaluate resting-state functional connectivity of targeted subcortical structures. Results: The functional connectivity between 2 region pairs demonstrated a significant correlation to PRS: right caudate–parietal cortex and nucleus accumbens–occipital cortex. Connectivity between these areas, in addition to being correlated with PRS, was correlated with ADHD status. The connection between the caudate and the parietal region acted as a statistical suppressor, such that when it was included in a path model, the association between PRS and ADHD status was enhanced. Conclusions: Our results suggest that functional connectivity to certain subcortical brain regions is directly altered by genetic variants, and certain cortico–subcortical connections may modulate ADHD-related genetic effects.