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
AU - Boomsma, Dorret I.
N1 - Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.
PY - 2016/10
Y1 - 2016/10
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 - Adolescent
KW - Attention Deficit Disorder with Hyperactivity/genetics
KW - Case-Control Studies
KW - Child
KW - Cohort Studies
KW - Female
KW - Genetics, Population/methods
KW - Genome-Wide Association Study
KW - Humans
KW - Journal Article
KW - Male
U2 - https://doi.org/10.1016/j.jaac.2016.05.025
DO - https://doi.org/10.1016/j.jaac.2016.05.025
M3 - Article
C2 - 27663945
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
M1 - 10
ER -
