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

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Acknowledgements

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.).

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Author notes

1. Josephine Elia and Joseph T Glessner: These authors contributed equally to this work.

Authors and Affiliations

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. Department of Psychiatry, Laboratory of Molecular Neuropsychiatry, 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. Department of Psychiatry, Attention Deficit Hyperactivity Disorder Clinical Research Network, Unit of Molecular 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. Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre, Donders Institute for Brain Cognition and Behaviour, 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. Department of Neurobehavioral Genetics, Institute of Psychobiology, 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

Authors

1. Josephine Elia
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2. Joseph T Glessner
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3. Kai Wang
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4. Nagahide Takahashi
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5. Corina J Shtir
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6. Dexter Hadley
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7. Patrick M A Sleiman
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8. Haitao Zhang
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9. Cecilia E Kim
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10. Reid Robison
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11. Gholson J Lyon
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12. James H Flory
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13. Jonathan P Bradfield
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14. Marcin Imielinski
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15. Cuiping Hou
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16. Edward C Frackelton
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17. Rosetta M Chiavacci
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18. Takeshi Sakurai
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19. Cara Rabin
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20. Frank A Middleton
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21. Kelly A Thomas
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22. Maria Garris
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23. Frank Mentch
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24. Christine M Freitag
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25. Hans-Christoph Steinhausen
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26. Alexandre A Todorov
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27. Andreas Reif
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28. Aribert Rothenberger
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29. Barbara Franke
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30. Eric O Mick
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31. Herbert Roeyers
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32. Jan Buitelaar
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33. Klaus-Peter Lesch
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34. Tobias Banaschewski
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35. Richard P Ebstein
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36. Fernando Mulas
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37. Robert D Oades
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38. Joseph Sergeant
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39. Edmund Sonuga-Barke
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40. Tobias J Renner
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41. Marcel Romanos
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42. Jasmin Romanos
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43. Andreas Warnke
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44. Susanne Walitza
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45. Jobst Meyer
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46. Haukur Pálmason
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47. Christiane Seitz
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48. Sandra K Loo
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49. Susan L Smalley
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50. Joseph Biederman
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51. Lindsey Kent
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52. Philip Asherson
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53. Richard J L Anney
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54. J William Gaynor
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55. Philip Shaw
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56. Marcella Devoto
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57. Peter S White
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58. Struan F A Grant
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59. Joseph D Buxbaum
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60. Judith L Rapoport
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61. Nigel M Williams
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62. Stanley F Nelson
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63. Stephen V Faraone
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64. 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.

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Correspondence toHakon Hakonarson.

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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.

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Elia, J., Glessner, J., Wang, K. et al. Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder.Nat Genet 44, 78–84 (2012). https://doi.org/10.1038/ng.1013

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• Received: 24 June 2011
• Accepted: 28 October 2011
• Published: 04 December 2011
• Issue Date: January 2012
• DOI: https://doi.org/10.1038/ng.1013