TY - JOUR
T1 - Differences in the genetic architecture of common and rare variants in childhood, persistent and late-diagnosed attention-deficit hyperactivity disorder
AU - Rajagopal, Veera M
AU - Duan, Jinjie
AU - Vilar-Ribó, Laura
AU - Grove, Jakob
AU - Zayats, Tetyana
AU - Ramos-Quiroga, J Antoni
AU - Satterstrom, F Kyle
AU - Artigas, María Soler
AU - Bybjerg-Grauholm, Jonas
AU - Bækvad-Hansen, Marie
AU - Als, Thomas D
AU - Rosengren, Anders
AU - Daly, Mark J
AU - Neale, Benjamin M
AU - Nordentoft, Merete
AU - Werge, Thomas
AU - Mors, Ole
AU - Hougaard, David M
AU - Mortensen, Preben B
AU - Ribasés, Marta
AU - Børglum, Anders D
AU - Demontis, Ditte
N1 - © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
KW - Adult
KW - Attention Deficit Disorder with Hyperactivity/diagnosis
KW - Comorbidity
KW - Genetic Predisposition to Disease
KW - Humans
KW - Multifactorial Inheritance
KW - Neurodevelopmental Disorders
UR - http://www.scopus.com/inward/record.url?scp=85135556379&partnerID=8YFLogxK
U2 - 10.1038/s41588-022-01143-7
DO - 10.1038/s41588-022-01143-7
M3 - Journal article
C2 - 35927488
SN - 1061-4036
VL - 54
SP - 1117
EP - 1124
JO - Nature Genetics
JF - Nature Genetics
IS - 8
ER -