A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts

Christel M Middeldorp, Anke R Hammerschlag, Klaasjan G Ouwens, Maria M Groen-Blokhuis, Beate St Pourcain, Corina U Greven, Irene Pappa, Carla M T Tiesler, Wei Ang, Ilja M Nolte, Natalia Vilor-Tejedor, Jonas Bacelis, Jane L Ebejer, Huiying Zhao, Gareth E Davies, Erik A Ehli, David M Evans, Iryna O Fedko, Mònica Guxens, Jouke-Jan HottengaJames J Hudziak, Astanand Jugessur, John P Kemp, Eva Krapohl, Nicholas G Martin, Mario Murcia, Ronny Myhre, Johan Ormel, Susan M Ring, Marie Standl, Evie Stergiakouli, Camilla Stoltenberg, Elisabeth Thiering, Nicholas J Timpson, Maciej Trzaskowski, Peter J van der Most, Carol Wang, Dale R Nyholt, Sarah E Medland, Benjamin Neale, Bo Jacobsson, Jordi Sunyer, Catharina A Hartman, Andrew J O Whitehouse, Craig E Pennell, Joachim Heinrich, Robert Plomin, George Davey Smith, Henning Tiemeier, Danielle Posthuma, EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium, Psychiatric Genomics Consortium ADHD Working Group

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

OBJECTIVE: The aims of this study were to elucidate the influence of common genetic variants on childhood attention-deficit/hyperactivity disorder (ADHD) symptoms, to identify genetic variants that explain its high heritability, and to investigate the genetic overlap of ADHD symptom scores with ADHD diagnosis.

METHOD: Within the EArly Genetics and Lifecourse Epidemiology (EAGLE) consortium, genome-wide single nucleotide polymorphisms (SNPs) and ADHD symptom scores were available for 17,666 children (<13 years of age) from nine population-based cohorts. SNP-based heritability was estimated in data from the three largest cohorts. Meta-analysis based on genome-wide association (GWA) analyses with SNPs was followed by gene-based association tests, and the overlap in results with a meta-analysis in the Psychiatric Genomics Consortium (PGC) case-control ADHD study was investigated.

RESULTS: SNP-based heritability ranged from 5% to 34%, indicating that variation in common genetic variants influences ADHD symptom scores. The meta-analysis did not detect genome-wide significant SNPs, but three genes, lying close to each other with SNPs in high linkage disequilibrium (LD), showed a gene-wide significant association (p values between 1.46 × 10(-6) and 2.66 × 10(-6)). One gene, WASL, is involved in neuronal development. Both SNP- and gene-based analyses indicated overlap with the PGC meta-analysis results with the genetic correlation estimated at 0.96.

CONCLUSION: The SNP-based heritability for ADHD symptom scores indicates a polygenic architecture, and genes involved in neurite outgrowth are possibly involved. Continuous and dichotomous measures of ADHD appear to assess a genetically common phenotype. A next step is to combine data from population-based and case-control cohorts in genetic association studies to increase sample size and to improve statistical power for identifying genetic variants.

Original languageEnglish
Pages (from-to)896-905.e6
JournalJournal of the American Academy of Child and Adolescent Psychiatry
Volume55
Issue number10
DOIs
Publication statusPublished - 2016

Cite this

Middeldorp, C. M., Hammerschlag, A. R., Ouwens, K. G., Groen-Blokhuis, M. M., St Pourcain, B., Greven, C. U., ... EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium, Psychiatric Genomics Consortium ADHD Working Group (2016). A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts. Journal of the American Academy of Child and Adolescent Psychiatry, 55(10), 896-905.e6. https://doi.org/10.1016/j.jaac.2016.05.025