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 to 0.054]). Additionally, 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.

Predicting the course of ADHD symptoms through the integration of childhood genomic, neural, and cognitive features

“…Earlier reports find that high polygenic risk for ADHD is associated with symptom persistence but did not consider the possibility that polygenic risk may be associated with a worsening symptom course, as we report 7 . This finding extends previous reports of cross-sectional associations between polygenic risk and clinical severity, cognition and academic impairment [32][33][34][35] . The potential prognostic utility of polygenic risk is likely to improve as increasingly large GWAS allow more refined measures of polygenic risk through stratification based on age.…”

Behavioural Measures of Infant Activity but Not Attention Associate with Later Preschool ADHD Traits

“…Preschool ADHD is predominantly defined by hyperactivity/impulsivity [ 33 ] and some have suggested that the DSM-defined subtypes of ADHD are not applicable to preschoolers [ 104 ], with rates of the hyperactive-impulsive subtype of ADHD decreasing in older children, and the rates of the combined or inattentive subtype of ADHD increasing [ 33 , 105 , 106 ]. Furthermore, polygenic scores for ADHD may be associated with symptoms of hyperactivity and impulsivity (but not inattention) [ 107 ]. Perhaps the genetic likelihood design of this study was therefore better suited to investigate pathways to hyperactive/impulsive behaviours than inattention.…”

The stress–Wnt-signaling axis: a hypothesis for attention-deficit hyperactivity disorder and therapy approaches

“…Indeed, the polygenic risk score (PRS) analysis summarizing statistically all the SNP results from a large genome-wide association study (GWAS) has shown some promising results 50 . For example, ADHD-PRS was found to associate with symptoms of hyperactivity-impulsivity and to be mediated by white matter microstructure in brain regions that have been suggested to have a role in ADHD pathology 51,52 . In addition, ADHD-PRS was found to predict educational achievement 53 , to be linked with the severity of the clinical profile in those with high PRS 54 , and even to predict MPH response 55 .…”