Letter | Published:

Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

Nature Genetics volume 44, pages 7884 (2012) | Download Citation


Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10−9). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10−6). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in 10% of the cases (P = 4.38 × 10−10) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

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We thank all the children with ADHD and their families who participated in this study and all the control subjects who donated blood samples to The Children's Hospital of Philadelphia (CHOP) for genetic research purposes. We thank the technical staff at the Center for Applied Genomics, CHOP for generating the genotypes used in this study and the medical assistants, and nursing and medical staff who recruited the subjects. We thank the Center for Biomedical Informatics for bioinformatics support. We also thank S. Kristinsson, L.A. Hermannsson and A. Krisbjörnsson for their software design and contribution to the study.

We thank the IMAGE, IMAGE II and PUWMa consortium investigators and the NIMH for making the genotype data available. Funding support for International Multi-Center ADHD Genetics (IMAGE) and IMAGE II Projects was provided by US National Institutes of Health (NIH) grant R01MH62873 to S.V.F., and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The dataset used for the IMAGE analyses described in this manuscript were obtained from the database of Genotype and Phenotype (dbGaP), which is found at http://www.ncbi.nlm.nih.gov/gap, through dbGaP accession numbers phs000016.v2.p2 (ADHD IMAGE), phs000020.v2.p1 (depression) and phs000019.v1.p1 (psoriasis). Samples and associated phenotype data for the GAIN Major Depression: Stage 1 Genome-wide Association In Population Based Samples Study (principal investigator, P.F. Sullivan, University of North Carolina) were provided by D.I. Boomsma and E. de Geus, Vrije Universiteit Amsterdam (principal investigators, Netherlands Twin Register); B.W. Penninx, Vrije Universiteit Medical Center Amsterdam; F. Zitman, Leiden University Medical Center, Leiden; and W. Nolen, University Medical Center Groningen (principal investigators and site principal investigators, Netherlands Study of Depression and Anxiety). Samples and associated phenotype data for the Collaborative Association Study of Psoriasis were provided by J.T. Elder (University of Michigan, Ann Arbor, Michigan), G.G. Krueger (University of Utah, Salt Lake City, Utah), A. Bowcock (Washington University, St. Louis, Missouri) and G.R. Abecasis (University of Michigan, Ann Arbor, Michigan). Samples and associated phenotype data for the International Multi-Center ADHD Genetics Project were provided by the following investigators: S.V.F. (principal investigator), R.J.L.A., P.A., J.S., R.P.E., B.F., M. Gill, A. Miranda, F. Mulas, R.D.O., H.R., A. Rothenberger, T.B., J. Buitelaar, E. Sonuga-Barke and H.-C.S. (site principal investigators), M. Daly, C. Lange, N. Laird, J. Su and B. Neale (statistical analysis team). Samples and associated phenotype data were accessed through an authorized data access request by H.H. and S.F.A.G. Data collection for the PUWMa sample was supported by NIH grants to S.V.F., J. Biederman, S. Smalley, R. Todd and A.A.T. GWAS genotyping of the PUWMa samples was completed by Genizon and was provided through a grant for genotyping services to S.V.F. The PUWMa consortium represents a Pfizer-funded collaboration among the University of California Los Angeles, Washington University and Massachussetts General Hospital. We thank M.C. O'Donovan, M. Gill, M.J. Owen, P.A. Holmans, A. Thapar, B.M. Neale and A. Miranda for contributing DNA samples and phenotypes to the study and for editing the manuscript. We thank G. DePalma, T. Töpner, A. Guiney and H. Zhang for providing samples for the qRT-PCR CNV validation.

The study was supported by an Institutional Development Award to the Center for Applied Genomics from CHOP (H.H.), which funded all of the discovery genome-wide genotyping for this study. This work was additionally supported in part by NIH grant K23MH066275 (J.E.), University of Pennsylvania National Center for Research Resources Clinical and Translational Science Awards grant UL1-RR-024134 (J.E.), by a Research Development Award from the Cotswold Foundation (H.H. and S.F.A.G.) and by US Department of Health and Human Services grant 1RC2MH089924 (H.H.). N.T., T.S. and J.D.B. received support from the Seaver Foundation and a Conte Center for Neuroscience of Mental Disorders grant from the NIMH (P50MH066392).

Sample and phenotype data collection of parts of the IMAGE II cohort was supported by the Deutsche Forschungsgemeinschaft (KFO 125, SFB 581 and SFB TRR 58 to K.-P.L. and A. Reif, ME 1923/5-1 and ME 1923/5-3 to C.M.F. and J.M.) and the Bundesministerium für Bildung und Forschung (BMBF 01GV0605 to K.-P.L.).

Author information

Author notes

    • Josephine Elia
    •  & Joseph T Glessner

    These authors contributed equally to this work.


  1. Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Josephine Elia
  2. Department of Child and Adolescent Psychiatry, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Josephine Elia
  3. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Joseph T Glessner
    • , Kai Wang
    • , Dexter Hadley
    • , Patrick M A Sleiman
    • , Haitao Zhang
    • , Cecilia E Kim
    • , James H Flory
    • , Jonathan P Bradfield
    • , Marcin Imielinski
    • , Cuiping Hou
    • , Edward C Frackelton
    • , Rosetta M Chiavacci
    • , Kelly A Thomas
    • , Maria Garris
    • , Frank Mentch
    • , Struan F A Grant
    •  & Hakon Hakonarson
  4. Laboratory of Molecular Neuropsychiatry, Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA.

    • Nagahide Takahashi
    • , Takeshi Sakurai
    •  & Joseph D Buxbaum
  5. Department of Human Genetics and Psychiatry, University of California Los Angeles, Los Angeles, California, USA.

    • Corina J Shtir
    •  & Stanley F Nelson
  6. Department of Psychiatry, University of Utah, Salt Lake City, Utah, USA.

    • Reid Robison
    •  & Gholson J Lyon
  7. Child Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland, USA.

    • Cara Rabin
    • , Philip Shaw
    •  & Judith L Rapoport
  8. Department of Neuroscience and Physiology, State University of New York Upstate Medical University, Syracuse, New York, USA.

    • Frank A Middleton
    •  & Stephen V Faraone
  9. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe University, Frankfurt am Main, Germany.

    • Christine M Freitag
  10. Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland.

    • Hans-Christoph Steinhausen
    • , Susanne Walitza
    •  & Philip Asherson
  11. Aalborg Psychiatric Hospital, Aarhus University Hospital, Aarhus, Denmark.

    • Hans-Christoph Steinhausen
  12. Institute of Psychology, University of Basel, Basel, Switzerland.

    • Hans-Christoph Steinhausen
  13. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Alexandre A Todorov
  14. Attention Deficit Hyperactivity Disorder Clinical Research Network, Unit of Molecular Psychiatry, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.

    • Andreas Reif
    •  & Klaus-Peter Lesch
  15. Child and Adolescent Psychiatry, University of Göttingen, Göttingen, Germany.

    • Aribert Rothenberger
  16. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Barbara Franke
  17. Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Barbara Franke
  18. Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Eric O Mick
    •  & Joseph Biederman
  19. Department of Experimental Clinical and Health Psychology, Ghent University, Ghent, Belgium.

    • Herbert Roeyers
  20. Radboud University Nijmegen Medical Centre, Donders Institute for Brain Cognition and Behaviour, Department of Cognitive Neuroscience, Nijmegen, The Netherlands.

    • Jan Buitelaar
  21. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany.

    • Tobias Banaschewski
  22. Department of Psychology, National University of Singapore, Queenstown, Singapore.

    • Richard P Ebstein
  23. Department of Neuropaediatrics, La Fe University Hospital, Faculty of Medicine, Valencia, Spain.

    • Fernando Mulas
  24. Clinic for Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.

    • Robert D Oades
  25. Vrije Universiteit, De Boelelaan, Amsterdam, The Netherlands.

    • Joseph Sergeant
  26. School of Psychology, Institute for Disorder on Impulse and Attention, University of Southampton, Highfield, Southampton, UK.

    • Edmund Sonuga-Barke
  27. Department of Experimental Clinical and Health Psychology, Ghent University, Dunantlaan, Ghent, Belgium.

    • Edmund Sonuga-Barke
  28. Child Study Center, New York University, New York, New York, USA.

    • Edmund Sonuga-Barke
  29. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, Würzburg, Germany.

    • Tobias J Renner
    • , Marcel Romanos
    • , Jasmin Romanos
    • , Andreas Warnke
    •  & Susanne Walitza
  30. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Munich, Munich, Germany.

    • Marcel Romanos
  31. Institute of Psychobiology, Department of Neurobehavioral Genetics, University of Trier, Trier, Germany.

    • Jobst Meyer
    •  & Haukur Pálmason
  32. Department of Child and Adolescent Psychiatry, Saarland University, Homburg, Germany.

    • Christiane Seitz
  33. Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, USA.

    • Sandra K Loo
    •  & Susan L Smalley
  34. Bute Medical School, St. Andrews, Scotland, UK.

    • Lindsey Kent
  35. Department of Psychiatry, Trinity Centre for Health Sciences, St. James's Hospital, Dublin, Ireland.

    • Richard J L Anney
  36. Division of Cardiothoracic Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • J William Gaynor
    •  & Hakon Hakonarson
  37. Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Marcella Devoto
    • , Struan F A Grant
    •  & Hakon Hakonarson
  38. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Marcella Devoto
    •  & Struan F A Grant
  39. Dipartimento di Medicina Sperimentale, University La Sapienza, Rome, Italy.

    • Marcella Devoto
  40. Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Marcella Devoto
  41. Center for Biomedical Informatics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Peter S White
  42. Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Peter S White
  43. Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, Wales, UK.

    • Nigel M Williams
  44. Department of Psychiatry, State University of New York Upstate Medical University, Syracuse, New York, USA.

    • Stephen V Faraone
  45. Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Hakon Hakonarson


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H.H. and J.E. designed the CHOP study and supervised the data analyses and interpretation. S.V.F., M.G., P.A. and J. Buitelaar designed the IMAGE and IMAGE II studies. S.V.F. designed the PUWMa study and coordinated the analyses for the IMAGE, IMAGE II and PUWMa studies. J.T.G. and K.W. conducted the statistical analyses. C.E.K. and E.C.F. directed the stage 1 genotyping. J.D.B. coordinated the validation analyses. N.T. performed the qRT-PCR validation of the CNVs. J.T.G. and H.H. drafted the manuscript. J.E. collected the CHOP samples. C.R., P.S. and J.L.R. collected the NIMH samples. C.M.F., H.-C.S., A.A.T., A. Reif, A. Rothenberger, B.F., E.O.M., H.R., J. Buitelaar, K.-P.L., L.K., T.B., R.P.E., F.M., R.D.O., J.S., E.S.-B., T.J.R., M.R., J.R., A.W., S.W., J.M., H.P., C.S., S.K.L., S.L.S., J. Biederman, L.K., P.A. and R.J.L.A. collected data for the IMAGE, IMAGE II and PUWMa projects. J. Biederman, E.O.M., S.V.F., S.K.L., S.L.S. and A.A.T. collected samples for the PUWMa study. F.A.M. genotyped the IMAGE II data. H.H. directed and D.H. and J.T.G. performed the gene interaction network and functional enrichment analyses. All authors contributed to the manuscript preparation. S.F.A.G. accessed the public domain data, assisted with the interpretation of the data and edited the manuscript. All other authors contributed samples and/or were involved with data mining and processing.

Competing interests

For the last 3 years, M.R. has been in the speakers' bureau for Janssen-Cilag. In previous years, he was on the speakers' bureau for MEDICE.

Corresponding author

Correspondence to Hakon Hakonarson.

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