Differences in the genetic architecture of common and rare variants in childhood, persistent and late-diagnosed attention deficit hyperactivity disorder

ABSTRACT Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder, with onset in childhood (“childhood ADHD”), and around two thirds of affected individuals will continue to have ADHD symptoms in adulthood (“persistent ADHD”). Age at first diagnosis can vary, and sometimes ADHD is first diagnosed in adulthood (“late-diagnosed ADHD”). In this study, we analyzed a large Danish population-based case-cohort generated by iPSYCH in order to identify common genetic risk loci and perform in-depth characterization of the polygenic architecture of childhood (N=14,878), persistent (N=1,473) and late-diagnosed ADHD (N=6,961) alongside 38,303 controls. Additionally, the burden of rare protein truncating variants in the three groups were evaluated in whole-exome sequencing data from a subset of the individuals (7,650 ADHD cases and 8,649 controls). We identified genome-wide significant loci associated with childhood ADHD (four loci) and late-diagnosed ADHD (one locus). In analyses of the polygenic architecture, we found higher polygenic score (PGS) of ADHD risk variants in persistent ADHD (mean PGS=0.41) compared to childhood (mean PGS=0.26) and late-diagnosed ADHD (mean PGS=0.27), and we found a significant decreased genetic correlation of late-diagnosed ADHD with inattention (r g =0.57) compared to childhood ADHD (r g =0.86). These results suggest that a higher ADHD polygenic risk burden is associated with persistence of symptoms, and that a later diagnosis of ADHD could be due in part to genetic factors. Additionally, childhood ADHD demonstrated both a significantly increased genetic overlap with autism compared to late-diagnosed ADHD as well as the highest burden of rare protein-truncating variants in highly constrained genes among ADHD subgroups (compared to controls: beta=0.13, P=2.41×10 −11 ). Late-diagnosed ADHD demonstrated significantly larger genetic overlap with depression than childhood ADHD and no increased burden in rare protein-truncating variants (compared to controls: beta=0.06). Overall, our study finds genetic heterogeneity among ADHD subgroups and suggests that genetic factors influence time of first ADHD diagnosis, persistence of ADHD and comorbidity patterns in the sub-groups.