Common and rare genetic variants explain distinct diagnostic variance in pediatric attention deficit hyperactivity disorder.

Abstract

Pediatric attention deficit hyperactivity disorder (ADHD, OMIM 143465) is highly heritable, yet the genetic architecture of the condition remains poorly understood. This study tested the hypothesis that rare and common genetic variants reflect distinct genetic pathways to ADHD. Genome sequencing was completed for 150 pediatric ADHD cases and 370 controls. ADHD polygenic scores were derived and compared across 5 methods, including 2 published genome-wide association studies and 2 publicly available catalogs. Likely pathogenic rare variants were identified with a previously published customized annotation and classification pipeline followed by manual curation using established American College of Medical Genetics and Genomics variant interpretation guidelines. 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 polygenic scores, ancestry, and rare variant status with 70% area under the curve. 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.