Common and Rare Genetic Variants Explain Distinct Diagnostic Variance in Pediatric Attention Deficit Hyperactivity Disorder.

Purpose: Pediatric attention deficit hyperactivity disorder (ADHD, MIM: 143465) is highly heritable, yet the genetic architecture of the condition remains poorly understood. The current study tested the hypothesis that rare and common genetic variants reflect distinct genetic pathways to ADHD.

Methods: Genome sequencing was completed for 150 pediatric ADHD cases and 370 controls. ADHD polygenic scores were derived and compared across five methods, including two published GWAS and two publicly available catalogs. Likely pathogenic rare variants were identified with a previously published customized annotation and classification pipeline followed by manual curation using established ACMGG variant interpretation guidelines.

Results: ADHD cases had higher ADHD polygenic scores and lower IQ polygenic scores. Likely pathogenic variants for ADHD were identified in 13% of cases and 0.5% of controls. ADHD polygenic scores among cases without rare variants were higher than cases carrying rare variants. ADHD cases were predicted by ADHD and IQ PGS, ancestry, and rare variant status with 70% area under the curve.

Conclusions: The genetic etiology of ADHD is likely multifactorial, with independent contributions from common and rare variants. Genome wide association studies of ADHD may have increased power to detect common genetic loci if individuals with rare variants are excluded.