A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Paediatric 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 Hottenga; James 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; Dorret I. Boomsma

doi:10.1016/j.jaac.2016.05.025

A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Paediatric 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, Dorret I. Boomsma

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Abstract

Objective

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) 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 improve statistical power for identifying genetic variants.

Original language	English
Pages (from-to)	896–905.e6
Journal	Journal of the American Academy of Child and Adolescent Psychiatry
Volume	55
Issue number	10
Early online date	5 Aug 2016
DOIs	https://doi.org/10.1016/j.jaac.2016.05.025
Publication status	Published - Oct 2016

Keywords

GWA
SNP heritability
attention problems
ADHD symptoms
meta-analysis

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10.1016/j.jaac.2016.05.025

A Genome-Wide Association Meta-Analysis_MIDDELDORP_Accepted29May2016_GREEN AAMAccepted author manuscript, 1.5 MBLicence: CC BY-NC-ND

Cite this

Middeldorp, C. M., Hammerschlag, A. R., Ouwens, K. G., Groen-Blokhuis, M. M., St. Pourcain, B., Greven, C. U., Pappa, I., Tiesler, C. M. T., Ang, W., Nolte, I. M., Vilor-Tejedor, N., Bacelis, J., Ebejer, J. L., Zhao, H., Davies, G. E., Ehli, E. A., Evans, D. M., Fedko, I. O., Guxens, M., ... Boomsma, D. I. (2016). A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Paediatric 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

@article{d43f816141b04bdaba5aa27c42934976,

title = "A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Paediatric Cohorts",

abstract = "ObjectiveTo 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.MethodWithin 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) 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.ResultsSNP-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.ConclusionThe 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 improve statistical power for identifying genetic variants.",

keywords = "GWA, SNP heritability, attention problems, ADHD symptoms, meta-analysis",

author = "Middeldorp, {Christel M.} and Hammerschlag, {Anke R.} and Ouwens, {Klaasjan G.} and Groen-Blokhuis, {Maria M.} and {St. Pourcain}, Beate and Greven, {Corina U.} and Irene Pappa and Tiesler, {Carla M.T.} and Wei Ang and Nolte, {Ilja M.} and Natalia Vilor-Tejedor and Jonas Bacelis and Ebejer, {Jane L.} and Huiying Zhao and Davies, {Gareth E.} and Ehli, {Erik A.} and Evans, {David M.} and Fedko, {Iryna O.} and M{\`o}nica Guxens and Jouke-Jan Hottenga and Hudziak, {James J.} and Astanand Jugessur and Kemp, {John P.} and Eva Krapohl and Martin, {Nicholas G.} and Mario Murcia and Ronny Myhre and Johan Ormel and Ring, {Susan M.} and Marie Standl and Evie Stergiakouli and Camilla Stoltenberg and Elisabeth Thiering and Timpson, {Nicholas J.} and Maciej Trzaskowski and {van der Most}, {Peter J.} and Carol Wang and Nyholt, {Dale R.} and Medland, {Sarah E.} and Benjamin Neale and Bo Jacobsson and Jordi Sunyer and Hartman, {Catharina A.} and Whitehouse, {Andrew J.O.} and Pennell, {Craig E.} and Joachim Heinrich and Robert Plomin and Smith, {George Davey} and Henning Tiemeier and Danielle Posthuma and Boomsma, {Dorret I.}",

year = "2016",

month = oct,

doi = "10.1016/j.jaac.2016.05.025",

language = "English",

volume = "55",

pages = "896–905.e6",

journal = "Journal of the American Academy of Child and Adolescent Psychiatry",

issn = "0890-8567",

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number = "10",

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Middeldorp, CM, Hammerschlag, AR, Ouwens, KG, Groen-Blokhuis, MM, St. Pourcain, B, Greven, CU, Pappa, I, Tiesler, CMT, Ang, W, Nolte, IM, Vilor-Tejedor, N, Bacelis, J, Ebejer, JL, Zhao, H, Davies, GE, Ehli, EA, Evans, DM, Fedko, IO, Guxens, M, Hottenga, J-J, Hudziak, JJ, Jugessur, A, Kemp, JP, Krapohl, E, Martin, NG, Murcia, M, Myhre, R, Ormel, J, Ring, SM, Standl, M, Stergiakouli, E, Stoltenberg, C, Thiering, E, Timpson, NJ, Trzaskowski, M, van der Most, PJ, Wang, C, Nyholt, DR, Medland, SE, Neale, B, Jacobsson, B, Sunyer, J, Hartman, CA, Whitehouse, AJO, Pennell, CE, Heinrich, J, Plomin, R, Smith, GD, Tiemeier, H, Posthuma, D & Boomsma, DI 2016, 'A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Paediatric Cohorts', Journal of the American Academy of Child and Adolescent Psychiatry, vol. 55, no. 10, pp. 896–905.e6. https://doi.org/10.1016/j.jaac.2016.05.025

A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Paediatric Cohorts. / Middeldorp, Christel M.; Hammerschlag, Anke R.; Ouwens, Klaasjan G. et al.
In: Journal of the American Academy of Child and Adolescent Psychiatry, Vol. 55, No. 10, 10.2016, p. 896–905.e6.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Paediatric Cohorts

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 - Smith, George Davey

AU - Tiemeier, Henning

AU - Posthuma, Danielle

AU - Boomsma, Dorret I.

PY - 2016/10

Y1 - 2016/10

N2 - ObjectiveTo 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.MethodWithin 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) 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.ResultsSNP-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.ConclusionThe 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 improve statistical power for identifying genetic variants.

AB - ObjectiveTo 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.MethodWithin 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) 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.ResultsSNP-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.ConclusionThe 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 improve statistical power for identifying genetic variants.

KW - GWA

KW - SNP heritability

KW - attention problems

KW - ADHD symptoms

KW - meta-analysis

U2 - 10.1016/j.jaac.2016.05.025

DO - 10.1016/j.jaac.2016.05.025

M3 - Article

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 -

Middeldorp CM, Hammerschlag AR, Ouwens KG, Groen-Blokhuis MM, St. Pourcain B, Greven CU et al. A Genome-Wide Association Meta-Analysis of Attention-Deficit/Hyperactivity Disorder Symptoms in Population-Based Paediatric Cohorts. Journal of the American Academy of Child and Adolescent Psychiatry. 2016 Oct;55(10):896–905.e6. Epub 2016 Aug 5. doi: 10.1016/j.jaac.2016.05.025

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

Abstract

Keywords

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