TY - JOUR
T1 - A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Pediatric Cohorts
AU - EArly Genetics and Lifecourse Epidemiology (EAGLE) Consortium, Psychiatric Genomics Consortium ADHD Working Group
AU - Middeldorp, Christel M.
AU - Hammerschlag, Anke R.
AU - Ouwens, Klaasjan G.
AU - Groen-Blokhuis, Maria M.
AU - St. Pourcain, Beate
AU - Greven, Corina U.
AU - Pappa, Irene
AU - Tiesler, Carla M.T.
AU - Ang, Wei
AU - Nolte, Ilja M.
AU - Vilor-Tejedor, Natalia
AU - Bacelis, Jonas
AU - Ebejer, Jane L.
AU - Zhao, Huiying
AU - Davies, Gareth E.
AU - Ehli, Erik A.
AU - Evans, David M.
AU - Fedko, Iryna O.
AU - Guxens, Mònica
AU - Hottenga, Jouke Jan
AU - Hudziak, James J.
AU - Jugessur, Astanand
AU - Kemp, John P.
AU - Krapohl, Eva
AU - Martin, Nicholas G.
AU - Murcia, Mario
AU - Myhre, Ronny
AU - Ormel, Johan
AU - Ring, Susan M.
AU - Standl, Marie
AU - Stergiakouli, Evie
AU - Stoltenberg, Camilla
AU - Thiering, Elisabeth
AU - Timpson, Nicholas J.
AU - Trzaskowski, Maciej
AU - van der Most, Peter J.
AU - Wang, Carol
AU - Nyholt, Dale R.
AU - Medland, Sarah E.
AU - Neale, Benjamin
AU - Jacobsson, Bo
AU - Sunyer, Jordi
AU - Hartman, Catharina A.
AU - Whitehouse, Andrew J.O.
AU - Pennell, Craig E.
AU - Heinrich, Joachim
AU - Plomin, Robert
AU - Davey Smith, George
AU - Tiemeier, Henning
AU - Posthuma, Danielle
N1 - Publisher Copyright:
© 2016 American Academy of Child and Adolescent Psychiatry
PY - 2016/9/21
Y1 - 2016/9/21
N2 - 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.
AB - 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.
KW - ADHD symptoms
KW - attention problems
KW - GWA
KW - meta-analysis
KW - SNP heritability
UR - https://www.scopus.com/pages/publications/84990861496
U2 - 10.1016/j.jaac.2016.05.025
DO - 10.1016/j.jaac.2016.05.025
M3 - Article
C2 - 27663945
AN - SCOPUS:84990861496
SN - 0890-8567
VL - 55
SP - 896-905.e6
JO - Journal of the American Academy of Child and Adolescent Psychiatry
JF - Journal of the American Academy of Child and Adolescent Psychiatry
IS - 10
ER -