Shared risk alleles with discordant polygenic effects: Disentangling the genetic overlap between ASD and ADHD

Insight into shared polygenetic architectures affects our understanding of neurodevelopmental disorders. Here, we investigate evidence for pleiotropic mechanisms that may explain the comorbidity between Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD). These complex neurodevelopmental conditions often co-occur, but differ in their polygenetic association patterns, especially with educational attainment (EA), showing discordant association effects. Using multivariable regression analyses and existing genome-wide summary statistics based on 10,610 to 766,345 individuals, we demonstrate that EA-related polygenic variation is shared between ASD and ADHD. We show that different combinations of the same ASD and ADHD risk-increasing alleles can simultaneously re-capture known ASD-related positive and ADHD-related negative associations with EA. Such patterns, although to a lesser degree, were also present for combinations of other psychiatric disorders. These findings suggest pleiotropic mechanisms, where the same polygenic sites can encode multiple independent, even discordant, association patterns without involving distinct loci, and have implications for cross-disorder investigations.