Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

TY - JOUR

T1 - Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

AU - Demontis, Ditte

AU - Walters, G Bragi

AU - Athanasiadis, Georgios

AU - Walters, Raymond

AU - Therrien, Karen

AU - Nielsen, Trine Tollerup

AU - Farajzadeh, Leila

AU - Voloudakis, Georgios

AU - Bendl, Jaroslav

AU - Zeng, Biau

AU - Zhang, Wen

AU - Grove, Jakob

AU - Als, Thomas D

AU - Duan, Jinjie

AU - Satterstrom, F Kyle

AU - Bybjerg-Grauholm, Jonas

AU - Bækved-Hansen, Marie

AU - Gudmundsson, Olafur O

AU - Magnusson, Sigurdur H

AU - Baldursson, Gisli

AU - Davidsdottir, Katrin

AU - Haraldsdottir, Gyda S

AU - Agerbo, Esben

AU - Hoffman, Gabriel E

AU - Dalsgaard, Søren

AU - Martin, Joanna

AU - Ribasés, Marta

AU - Boomsma, Dorret I

AU - Soler Artigas, Maria

AU - Roth Mota, Nina

AU - Howrigan, Daniel

AU - Medland, Sarah E

AU - Zayats, Tetyana

AU - Rajagopal, Veera M

AU - Nordentoft, Merete

AU - Mors, Ole

AU - Hougaard, David M

AU - Mortensen, Preben Bo

AU - Daly, Mark J

AU - Faraone, Stephen V

AU - Stefansson, Hreinn

AU - Roussos, Panos

AU - Franke, Barbara

AU - Werge, Thomas

AU - Neale, Benjamin M

AU - Stefansson, Kari

AU - Børglum, Anders D

AU - ADHD Working Group of the Psychiatric Genomics Consortium

PY - 2023/2

Y1 - 2023/2

N2 - Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.

AB - Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.

KW - Attention Deficit Disorder with Hyperactivity/genetics

KW - Brain

KW - Cognition

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

U2 - 10.1038/s41588-022-01285-8

DO - 10.1038/s41588-022-01285-8

M3 - Journal article

C2 - 36702997

SN - 1061-4036

VL - 55

SP - 198

EP - 208

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -