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 | |
| State | Published - Sep 2010 |
Keywords
- ADHD
- GWAS
- association
- genetics
- meta-analysis
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Meta-analysis of genome-wide association studies of attention-deficit/ hyperactivity disorder. / Neale, Benjamin M.; Medland, Sarah E.; Ripke, Stephan; Asherson, Philip; Franke, Barbara; Lesch, Klaus Peter; Faraone, Stephen V.; Nguyen, Thuy Trang; Schäfer, Helmut; Holmans, Peter; Daly, Mark; Steinhausen, Hans Christoph; Freitag, Christine; Reif, Andreas; Renner, Tobias J.; Romanos, Marcel; Romanos, Jasmin; Walitza, Susanne; Warnke, Andreas; Meyer, Jobst; Palmason, Haukur; Buitelaar, Jan; Vasquez, Alejandro Arias; Lambregts-Rommelse, Nanda; Gill, Michael; Anney, Richard J.L.; Langely, Kate; O'Donovan, Michael; Williams, Nigel; Owen, Michael; Thapar, Anita; Kent, Lindsey; Sergeant, Joseph; Roeyers, Herbert; Mick, Eric; Biederman, Joseph; Doyle, Alysa; Smalley, Susan; Loo, Sandra; Hakonarson, Hakon; Elia, Josephine; Todorov, Alexandre; Miranda, Ana; Mulas, Fernando; Ebstein, Richard P.; Rothenberger, Aribert; Banaschewski, Tobias; Oades, Robert D.; Sonuga-Barke, Edmund; McGough, James; Nisenbaum, Laura; Middleton, Frank; Hu, Xiaolan; Nelson, Stan.
In: Journal of the American Academy of Child and Adolescent Psychiatry, Vol. 49, No. 9, 09.2010, p. 884-897.Research output: Contribution to journal › Article › peer-review
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 - Schäfer, 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 - Nisenbaum, Laura
AU - Middleton, Frank
AU - Hu, Xiaolan
AU - Nelson, Stan
N1 - Funding Information: 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). Additional analytical support was from Foundation for the NIH and R01MH080403 (PI Sullivan). All computational work was conducted on the Genetic Cluster Computer (the Netherlands) which is funded by an NWO Medium Investment grant ( 480-05-003 , PI Posthuma), the Faculty of Psychology and Education of VU University (Amsterdam), and by the Dutch Brain Foundation (PI Ophoff) and is hosted by the Dutch National Computing and Networking Services. Funding Information: Disclosure: Dr. Buitelaar has, in the past 3 years, served as a consultant to, member of the advisory board, and/or served on the speakers' bureau for Janssen Cilag BV, Eli Lilly and Co., Bristol-Myers Squibb, Organon/Shering Plough, UCB, Shire, Medice, and Servier. Dr. Faraone has, in the past year, received consulting fees and has served on advisory boards for Eli Lilly and Co., Ortho-McNeil, and Shire Development, and has received research support from Eli Lilly and Co. , Pfizer , Shire , and the National Institutes of Health . In previous years, Dr. Faraone has received consulting fees, served on advisory boards, or been a speaker for Shire, McNeil, Janssen, Novartis, Pfizer, and Eli Lilly and Co. In previous years he has received research support from Eli Lilly and Co. , Shire , Pfizer , and the National Institutes of Health . Dr. Banaschewski has served on the Advisory Board or as a consultant for Desitin, Eli Lilly and Co., Medice, Novartis, Pfizer, Shire, UCB, and Viforpharma. He received conference attendance support or served on the speakers' bureau for Eli Lilly and Co., Janssen McNeil, Medice, Novartis, and UCB. He is or has been involved in clinical trials conducted by Eli Lilly and Co., Shire, and Novartis. The present work is unrelated to the above grants and relationships. Dr. M. Romanos, in the past three years, has served on the speakers' bureau for Janssen-Cilag. In previous years he has served on the speakers' bureau for Medice. Dr. Freitag, in the past 3 years, has served on the speakers' bureau for Eli-Lilly and Co., Shire, Novartis, and Janssen-Cilag. Dr. Mick receives research support from Ortho-McNeil Janssen Scientific Affairs , Pfizer , and Shire Pharmaceuticals , and has been an advisory board member for Shire Pharmaceuticals. Dr. Biederman receives research support from Alza , AstraZeneca , Bristol Myers Squibb , Eli Lilly and Co. , Janssen Pharmaceuticals Inc. , McNeil , Merck , Organon , Otsuka , Shire , the National Institute of Mental Health , and the National Institute of Child Health and Human Development . In 2009, Dr. Biederman served on the speakers' bureau for Fundacion Areces, Medice Pharmaceuticals, and the Spanish Child Psychiatry Association. In previous years, Dr. Biederman has received research support, consultation fees, or speaker's fees for/from Abbott , AstraZeneca , Celltech , Cephalon , Eli Lilly and Co. , Esai , Forest , Glaxo , Gliatech , Janssen , McNeil , the National Alliance for Research on Schizophrenia and Depression , the National Institute on Drug Abuse , New River , Novartis , Noven , Neurosearch , Pfizer , Pharmacia , the Prechter Foundation , Shire , the Stanley Foundation , UCB Pharma, Inc. , and Wyeth . Dr. Sergeant has served on the advisory boards for Eli Lilly and Co. and Shire. He has received research grant support from Eli Lilly and Co. and served on the speakers' bureau for Shire, Eli Lilly and Co., Janssen-Cilag, and Novartis. Dr. Oades has received research support from UCB GmbH , Janssen-Cilag , and Shire . Dr. Schäfer has served as a consultant for Daiichi Sankyo, served on the speakers' bureau for the European School of Oncology, and receives research grants from the German Federal Government and the German Research Foundation . Drs. Neale, Medland, Ripke, Asherson, Franke, Lesch, Nguyen, Holmans, Daly, Steinhausen, Reif, Renner, J. Romanos, Walitza, Warnke, Meyer, Palmason, Vasquez, Lambregts-Rommelse, Gill, Anney, Langely, O'Donovan, Williams, Owen, Thapar, Kent, Roeyers, Doyle, Smalley, Loo, Hakonarson, Elia, Todorov, Miranda, Mulas, Ebstein, Rothenberger, Sonuga-Barke, McGough, Nisenbaum, Middleton, Hu, and Nelson report no biomedical financial interests or potential conflicts of interest.
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 - GWAS
KW - association
KW - genetics
KW - meta-analysis
UR - http://www.scopus.com/inward/record.url?scp=77956178166&partnerID=8YFLogxK
U2 - 10.1016/j.jaac.2010.06.008
DO - 10.1016/j.jaac.2010.06.008
M3 - Article
C2 - 20732625
AN - SCOPUS:77956178166
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
SN - 0890-8567
IS - 9
ER -