Mapping associations between polygenic risks for childhood neuropsychiatric disorders, symptoms of attention deficit hyperactivity disorder, cognition, and the brain

Abstract

There are now large-scale data on which common genetic variants confer risk for attention deficit hyperactivity disorder (ADHD). Here, we use mediation analyses to explore how cognitive and neural features might explain the association between common variant (polygenic) risk for ADHD and its core symptoms. In total, 544 participants participated (mean 21 years, 212 (39%) with ADHD), most with cognitive assessments, neuroanatomic imaging, and imaging of white matter tract microstructure. We found that polygenic risk for ADHD was associated with symptoms of hyperactivity-impulsivity but not inattention. This association was mediated across multiple PRS thresholds by white matter microstructure, specifically by axial diffusivity of the right corona radiata, (maximum indirect effect β = -0.034 (CI: -0.065 to -0.01), by thickness of the left dorsomedial prefrontal (β = -0.029; CI: -0.061 to -0.0047) and area of the right lateral temporal cortex (β = 0.024; CI: 0.0034-0.054). In addition, modest serial mediation was found, mapping a pathway from polygenic risk, to white matter microstructure of the anterior corona radiata, then cognition (working memory, focused attention), and finally to hyperactivity-impulsivity (working memory β = -0.014 (CI: -0.038 to -0.0026); focused attention β = -0.011 (CI: -0.033 to -0.0017). These mediation pathways were diagnostically specific and were not found for polygenic risk for ASD or schizophrenia. In conclusion, using a deeply phenotyped cohort, we delineate a pathway from polygenic risk for ADHD to hyperactive-impulsive symptoms through white matter microstructure, cortical anatomy, and cognition.

Figure 1:

Figures showing mediation by white matter microstructure and cortical anatomy of the association betweenpolygenic risk (at PRS<0.1) for ADHD and hyperactive-impulsive symptoms. The indirect effect is the product of thepathway from polygenic risk to the candidate mediator, and the pathway from the mediator to hyperactivityimpulsivity.The direct effect of PRS on symptoms refers to the regression of PRS on symptoms after taking intoaccount the proposed mediator. The top panel shows mediation by white matter microstructure (axial diffusivity) ofthe regions in red. The middle panel illustrates mediation by the thickness of the left dorsomedial prefrontal cortex,and the lower panel, mediation by the surface area of the right lateral temporal cortex. Full results are given in Table 2.

Figure 2:

Serial mediation of the association between polygenic risk for ADHD and hyperactivity-impulsivity.Polygenic risk was linked with neural features, cognition (here showing working memory) and hyperactivityimpulsivity.Top panel shows mediation by the axial diffusivity of a region in the right anterior coronaradiata, the lower by the thickness of the left dorsomedial prefrontal cortex. Serial mediation explained 17% and 37% of the total genetic effect respectively. Full results in Supplemental Tables B8 and B9.