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

Veera M Rajagopal, Jinjie Duan, Laura Vilar-Ribó, Jakob Grove, Tetyana Zayats, J Antoni Ramos-Quiroga, F Kyle Satterstrom, María Soler Artigas, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Thomas D Als, Anders Rosengren, Mark J Daly, Benjamin M Neale, Merete Nordentoft, Thomas Werge, Ole Mors, David M Hougaard, Preben B Mortensen, Marta RibasésAnders D Børglum, Ditte Demontis

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with onset in childhood (childhood ADHD); two-thirds of affected individuals continue to have ADHD in adulthood (persistent ADHD), and sometimes ADHD is diagnosed in adulthood (late-diagnosed ADHD). We evaluated genetic differences among childhood (n = 14,878), persistent (n = 1,473) and late-diagnosed (n = 6,961) ADHD cases alongside 38,303 controls, and rare variant differences in 7,650 ADHD cases and 8,649 controls. We identified four genome-wide significant loci for childhood ADHD and one for late-diagnosed ADHD. We found increased polygenic scores for ADHD in persistent ADHD compared with the other two groups. Childhood ADHD had higher genetic overlap with hyperactivity and autism compared with late-diagnosed ADHD and the highest burden of rare protein-truncating variants in evolutionarily constrained genes. Late-diagnosed ADHD had a larger genetic overlap with depression than childhood ADHD and no increased burden in rare protein-truncating variants. Overall, these results suggest a genetic influence on age at first ADHD diagnosis, persistence of ADHD and the different comorbidity patterns among the groups.

Original languageEnglish
JournalNature Genetics
Volume54
Issue number8
Pages (from-to)1117-1124
Number of pages8
ISSN1061-4036
DOIs
Publication statusPublished - Aug 2022

Keywords

  • Adult
  • Attention Deficit Disorder with Hyperactivity/diagnosis
  • Comorbidity
  • Genetic Predisposition to Disease
  • Humans
  • Multifactorial Inheritance
  • Neurodevelopmental Disorders

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