Dataset Information

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.

ABSTRACT: Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

SUBMITTER: Demontis D

PROVIDER: S-EPMC6481311 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.

Demontis Ditte D Walters Raymond K RK Martin Joanna J Mattheisen Manuel M Als Thomas D TD Agerbo Esben E Baldursson Gísli G Belliveau Rich R Bybjerg-Grauholm Jonas J Bækvad-Hansen Marie M Cerrato Felecia F Chambert Kimberly K Churchhouse Claire C Dumont Ashley A Eriksson Nicholas N Gandal Michael M Goldstein Jacqueline I JI Grasby Katrina L KL Grove Jakob J Gudmundsson Olafur O OO Hansen Christine S CS Hauberg Mads Engel ME Hollegaard Mads V MV Howrigan Daniel P DP Huang Hailiang H Maller Julian B JB Martin Alicia R AR Martin Nicholas G NG Moran Jennifer J Pallesen Jonatan J Palmer Duncan S DS Pedersen Carsten Bøcker CB Pedersen Marianne Giørtz MG Poterba Timothy T Poulsen Jesper Buchhave JB Ripke Stephan S Robinson Elise B EB Satterstrom F Kyle FK Stefansson Hreinn H Stevens Christine C Turley Patrick P Walters G Bragi GB Won Hyejung H Wright Margaret J MJ Andreassen Ole A OA Asherson Philip P Burton Christie L CL Boomsma Dorret I DI Cormand Bru B Dalsgaard Søren S Franke Barbara B Gelernter Joel J Geschwind Daniel D Hakonarson Hakon H Haavik Jan J Kranzler Henry R HR Kuntsi Jonna J Langley Kate K Lesch Klaus-Peter KP Middeldorp Christel C Reif Andreas A Rohde Luis Augusto LA Roussos Panos P Schachar Russell R Sklar Pamela P Sonuga-Barke Edmund J S EJS Sullivan Patrick F PF Thapar Anita A Tung Joyce Y JY Waldman Irwin D ID Medland Sarah E SE Stefansson Kari K Nordentoft Merete M Hougaard David M DM Werge Thomas T Mors Ole O Mortensen Preben Bo PB Daly Mark J MJ Faraone Stephen V SV Børglum Anders D AD Neale Benjamin M BM

Nature genetics 20181126 1

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new inform ...[more]

PMID: 30478444

Similar Datasets

Project description:BackgroundAttention deficit hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric condition, but it has been difficult to identify genes underlying this disorder. This study aimed to explore genetics of ADHD in an ethnically homogeneous Norwegian population by means of a genome-wide association (GWA) analysis followed by examination of candidate loci.Materials and methodsParticipants were recruited through Norwegian medical and birth registries as well as the general population. Presence of ADHD was defined according to DSM-IV criteria. Genotyping was performed using Illumina Human OmniExpress-12v1 microarrays. Statistical analyses were divided into several steps: (1) genome-wide association in the form of logistic regression in PLINK and follow-up pathway analyses performed in DAPPLE and INRICH softwares, (2) SNP-heritability calculated using genome-wide complex trait analysis (GCTA) tool, (3) gene-based association tests carried out in JAG software, and (4) evaluation of previously reported genome-wide signals and candidate genes of ADHD.ResultsIn total, 1.358 individuals (478 cases and 880 controls) and 598.384 autosomal SNPs were subjected to GWA analysis. No single polymorphism reached genome-wide significance. The strongest signal was observed at rs9949006 in the ENSG00000263745 gene (OR=1.51, 95% CI 1.28-1.79, p=1.38E-06). Pathway analyses of the top SNPs implicated genes involved in the regulation of gene expression, cell adhesion and inflammation. Among previously identified ADHD candidate genes, prominent association signals were observed for SLC9A9 (rs1393072, OR=1.46, 95% CI = 1.21-1.77, p=9.95E-05) and TPH2 (rs17110690, OR = 1.38, 95% CI = 1.14-1.66, p=8.31E-04).ConclusionThis study confirms the complexity and heterogeneity of ADHD etiology. Taken together with previous findings, our results point to a spectrum of biological mechanisms underlying the symptoms of ADHD, providing targets for further genetic exploration of this complex disorder.

Dataset Information

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.

Publications

Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets