Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder

Benjamin M. Neale; Sarah E. Medland; Stephan Ripke; Philip Asherson; Barbara Franke; Klaus-Peter Lesch; Stephen V. Faraone; Thuy Trang Nguyen; Helmut Schaefer; Peter Holmans; Mark Daly; Hans-Christoph Steinhausen; Christine Freitag; Andreas Reif; Tobias J. Renner; Marcel Romanos; Jasmin Romanos; Susanne Walitza; Andreas Warnke; Jobst Meyer; Haukur Palmason; Jan Buitelaar; Alejandro Arias Vasquez; Nanda Lambregts-Rommelse; Michael Gill; Richard J. L. Anney; Kate Langely; Michael O'Donovan; Nigel Williams; Michael Owen; Anita Thapar; Lindsey Kent; Joseph Sergeant; Herbert Roeyers; Eric Mick; Joseph Biederman; Alysa Doyle; Susan Smalley; Sandra Loo; Hakon Hakonarson; Josephine Elia; Alexandre Todorov; Ana Miranda; Fernando Mulas; Richard P. Ebstein; Aribert Rothenberger; Tobias Banaschewski; Robert D. Oades; Edmund Sonuga-Barke; James McGough; Psychiat GWAS Consortium ADHD Subg

doi:10.1016/j.jaac.2010.06.008

Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder

Benjamin M. Neale, Sarah E. Medland, Stephan Ripke, Philip Asherson, Barbara Franke, Klaus-Peter Lesch, Stephen V. Faraone, Thuy Trang Nguyen, Helmut Schaefer, Peter Holmans, Mark Daly, Hans-Christoph Steinhausen, Christine Freitag, Andreas Reif, Tobias J. Renner, Marcel Romanos, Jasmin Romanos, Susanne Walitza, Andreas Warnke, Jobst MeyerHaukur Palmason, Jan Buitelaar, Alejandro Arias Vasquez, Nanda Lambregts-Rommelse, Michael Gill, Richard J. L. Anney, Kate Langely, Michael O'Donovan, Nigel Williams, Michael Owen, Anita Thapar, Lindsey Kent, Joseph Sergeant, Herbert Roeyers, Eric Mick, Joseph Biederman, Alysa Doyle, Susan Smalley, Sandra Loo, Hakon Hakonarson, Josephine Elia, Alexandre Todorov, Ana Miranda, Fernando Mulas, Richard P. Ebstein, Aribert Rothenberger, Tobias Banaschewski, Robert D. Oades, Edmund Sonuga-Barke, James McGough, Psychiat GWAS Consortium ADHD Subg

School of Medicine

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

Abstract

Objective

Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power.

Method

We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis.

Results

No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder.

Conclusions

Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability.

Original language	English
Pages (from-to)	884-897
Number of pages	14
Journal	Journal of the American Academy of Child and Adolescent Psychiatry
Volume	49
Issue number	9
DOIs	https://doi.org/10.1016/j.jaac.2010.06.008
Publication status	Published - Sept 2010

Keywords

ADHD
Meta-analysis
Association
GWAS
Genetics

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10.1016/j.jaac.2010.06.008

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Neale, B. M., Medland, S. E., Ripke, S., Asherson, P., Franke, B., Lesch, K.-P., Faraone, S. V., Nguyen, T. T., Schaefer, H., Holmans, P., Daly, M., Steinhausen, H.-C., Freitag, C., Reif, A., Renner, T. J., Romanos, M., Romanos, J., Walitza, S., Warnke, A., ... Psychiat GWAS Consortium ADHD Subg (2010). Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 49(9), 884-897. https://doi.org/10.1016/j.jaac.2010.06.008

@article{e07211e957df4905b95c33fc0a40d6b5,

title = "Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder",

abstract = "Objective Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. Results No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. Conclusions Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability.",

keywords = "ADHD, Meta-analysis, Association, GWAS, Genetics",

author = "Neale, {Benjamin M.} and Medland, {Sarah E.} and Stephan Ripke and Philip Asherson and Barbara Franke and Klaus-Peter Lesch and Faraone, {Stephen V.} and Nguyen, {Thuy Trang} and Helmut Schaefer and Peter Holmans and Mark Daly and Hans-Christoph Steinhausen and Christine Freitag and Andreas Reif and Renner, {Tobias J.} and Marcel Romanos and Jasmin Romanos and Susanne Walitza and Andreas Warnke and Jobst Meyer and Haukur Palmason and Jan Buitelaar and Vasquez, {Alejandro Arias} and Nanda Lambregts-Rommelse and Michael Gill and Anney, {Richard J. L.} and Kate Langely and Michael O'Donovan and Nigel Williams and Michael Owen and Anita Thapar and Lindsey Kent and Joseph Sergeant and Herbert Roeyers and Eric Mick and Joseph Biederman and Alysa Doyle and Susan Smalley and Sandra Loo and Hakon Hakonarson and Josephine Elia and Alexandre Todorov and Ana Miranda and Fernando Mulas and Ebstein, {Richard P.} and Aribert Rothenberger and Tobias Banaschewski and Oades, {Robert D.} and Edmund Sonuga-Barke and James McGough and {Psychiat GWAS Consortium ADHD Subg}",

note = "Funding: This project was supported by the following grants: US National of Institute of Health Grants R13MH059126, R01MH62873, U01MH085518 and R01MH081803 to S.V. Faraone, U01MH085515 to M. Daly K23MH066275-01 to J. Elia; and R01MH58277 to S. Smalley; Institutional Development Award to the Center for Applied Genomics from the Children's Hospital of Philadelphia to H. Hakonarson. Affymetrix Power Award, 2007 to B. Franke; NHMRC (Australia) and Sidney Sax Public Health Fellowship (443036) to S.E. Medland; Wellcome Trust, UK for sample collection to L Kent. UMC Utrecht Genvlag Grant and Internal Grant of Radboud University, Nijmegen Medical Centre to J. Buitelaar, the Deutsche Forschungsgemeinschaft (KFO 125, SFB 581, GRK 1156 to K.P. Lesch, ME 1923/5-1, ME 1923/5-3, GRK 1389 to C. Freitag and J. Meyer, SCHA 542/10-3 to H. Sch{\"a}fer) and the Bundesministerium f{\"u}r Bildung und Forschung (BMBF 01GV0605 to K.P. Lesch).",

year = "2010",

month = sep,

doi = "10.1016/j.jaac.2010.06.008",

language = "English",

volume = "49",

pages = "884--897",

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

publisher = "Elsevier",

number = "9",

}

Neale, BM, Medland, SE, Ripke, S, Asherson, P, Franke, B, Lesch, K-P, Faraone, SV, Nguyen, TT, Schaefer, H, Holmans, P, Daly, M, Steinhausen, H-C, Freitag, C, Reif, A, Renner, TJ, Romanos, M, Romanos, J, Walitza, S, Warnke, A, Meyer, J, Palmason, H, Buitelaar, J, Vasquez, AA, Lambregts-Rommelse, N, Gill, M, Anney, RJL, Langely, K, O'Donovan, M, Williams, N, Owen, M, Thapar, A, Kent, L, Sergeant, J, Roeyers, H, Mick, E, Biederman, J, Doyle, A, Smalley, S, Loo, S, Hakonarson, H, Elia, J, Todorov, A, Miranda, A, Mulas, F, Ebstein, RP, Rothenberger, A, Banaschewski, T, Oades, RD, Sonuga-Barke, E, McGough, J & Psychiat GWAS Consortium ADHD Subg 2010, 'Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder', Journal of the American Academy of Child and Adolescent Psychiatry, vol. 49, no. 9, pp. 884-897. https://doi.org/10.1016/j.jaac.2010.06.008

TY - JOUR

T1 - Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder

AU - Neale, Benjamin M.

AU - Medland, Sarah E.

AU - Ripke, Stephan

AU - Asherson, Philip

AU - Franke, Barbara

AU - Lesch, Klaus-Peter

AU - Faraone, Stephen V.

AU - Nguyen, Thuy Trang

AU - Schaefer, Helmut

AU - Holmans, Peter

AU - Daly, Mark

AU - Steinhausen, Hans-Christoph

AU - Freitag, Christine

AU - Reif, Andreas

AU - Renner, Tobias J.

AU - Romanos, Marcel

AU - Romanos, Jasmin

AU - Walitza, Susanne

AU - Warnke, Andreas

AU - Meyer, Jobst

AU - Palmason, Haukur

AU - Buitelaar, Jan

AU - Vasquez, Alejandro Arias

AU - Lambregts-Rommelse, Nanda

AU - Gill, Michael

AU - Anney, Richard J. L.

AU - Langely, Kate

AU - O'Donovan, Michael

AU - Williams, Nigel

AU - Owen, Michael

AU - Thapar, Anita

AU - Kent, Lindsey

AU - Sergeant, Joseph

AU - Roeyers, Herbert

AU - Mick, Eric

AU - Biederman, Joseph

AU - Doyle, Alysa

AU - Smalley, Susan

AU - Loo, Sandra

AU - Hakonarson, Hakon

AU - Elia, Josephine

AU - Todorov, Alexandre

AU - Miranda, Ana

AU - Mulas, Fernando

AU - Ebstein, Richard P.

AU - Rothenberger, Aribert

AU - Banaschewski, Tobias

AU - Oades, Robert D.

AU - Sonuga-Barke, Edmund

AU - McGough, James

AU - Psychiat GWAS Consortium ADHD Subg

N1 - Funding: This project was supported by the following grants: US National of Institute of Health Grants R13MH059126, R01MH62873, U01MH085518 and R01MH081803 to S.V. Faraone, U01MH085515 to M. Daly K23MH066275-01 to J. Elia; and R01MH58277 to S. Smalley; Institutional Development Award to the Center for Applied Genomics from the Children's Hospital of Philadelphia to H. Hakonarson. Affymetrix Power Award, 2007 to B. Franke; NHMRC (Australia) and Sidney Sax Public Health Fellowship (443036) to S.E. Medland; Wellcome Trust, UK for sample collection to L Kent. UMC Utrecht Genvlag Grant and Internal Grant of Radboud University, Nijmegen Medical Centre to J. Buitelaar, the Deutsche Forschungsgemeinschaft (KFO 125, SFB 581, GRK 1156 to K.P. Lesch, ME 1923/5-1, ME 1923/5-3, GRK 1389 to C. Freitag and J. Meyer, SCHA 542/10-3 to H. Schäfer) and the Bundesministerium für Bildung und Forschung (BMBF 01GV0605 to K.P. Lesch).

PY - 2010/9

Y1 - 2010/9

N2 - Objective Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. Results No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. Conclusions Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability.

AB - Objective Although twin and family studies have shown attention-deficit/hyperactivity disorder (ADHD) to be highly heritable, genetic variants influencing the trait at a genome-wide significant level have yet to be identified. As prior genome-wide association studies (GWAS) have not yielded significant results, we conducted a meta-analysis of existing studies to boost statistical power. Method We used data from four projects: a) the Children's Hospital of Philadelphia (CHOP); b) phase I of the International Multicenter ADHD Genetics project (IMAGE); c) phase II of IMAGE (IMAGE II); and d) the Pfizer-funded study from the University of California, Los Angeles, Washington University, and Massachusetts General Hospital (PUWMa). The final sample size consisted of 2,064 trios, 896 cases, and 2,455 controls. For each study, we imputed HapMap single nucleotide polymorphisms, computed association test statistics and transformed them to z-scores, and then combined weighted z-scores in a meta-analysis. Results No genome-wide significant associations were found, although an analysis of candidate genes suggests that they may be involved in the disorder. Conclusions Given that ADHD is a highly heritable disorder, our negative results suggest that the effects of common ADHD risk variants must, individually, be very small or that other types of variants, e.g., rare ones, account for much of the disorder's heritability.

KW - ADHD

KW - Meta-analysis

KW - Association

KW - GWAS

KW - Genetics

U2 - 10.1016/j.jaac.2010.06.008

DO - 10.1016/j.jaac.2010.06.008

M3 - Article

VL - 49

SP - 884

EP - 897

JO - Journal of the American Academy of Child and Adolescent Psychiatry

JF - Journal of the American Academy of Child and Adolescent Psychiatry

IS - 9

ER -

Meta-analysis of genome-wide association studies of attention-deficit/hyperactivity disorder

Abstract

Keywords

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