Journal of the American Academy of Child & Adolescent Psychiatry
Volume 49, Issue 9 , Pages 898-905.e3 , September 2010

Family-Based Genome-Wide Association Scan of Attention-Deficit/Hyperactivity Disorder

  • Eric Mick, Sc.D.

      Affiliations

    • Massachusetts General Hospital and Harvard Medical School, Boston, MA
    • Corresponding Author InformationCorrespondence to Eric Mick, Sc.D., Massachusetts General Hospital, 55 Fruit Street—Warren 705, Boston, MA 02114
    • ,
  • Alexandre Todorov, Ph.D.

      Affiliations

    • Washington University School of Medicine, St. Louis, MO
    • ,
  • Susan Smalley, Ph.D.

      Affiliations

    • University of California Los Angeles
    • ,
  • Xiaolan Hu, Ph.D.

      Affiliations

    • Molecular Medicine, Pfizer Inc
    • ,
  • Sandra Loo, Ph.D.

      Affiliations

    • University of California Los Angeles
    • ,
  • Richard D. Todd, M.D.

      Affiliations

    • Washington University School of Medicine, St. Louis, MO
    • ,
  • Joseph Biederman, M.D.

      Affiliations

    • Massachusetts General Hospital and Harvard Medical School, Boston, MA
    • ,
  • Deirdre Byrne, B.S.

      Affiliations

    • Massachusetts General Hospital and Harvard Medical School, Boston, MA
    • ,
  • Bryan Dechairo, Ph.D.

      Affiliations

    • Molecular Medicine, Pfizer Inc
    • ,
  • Allan Guiney, B.A.

      Affiliations

    • Massachusetts General Hospital and Harvard Medical School, Boston, MA
    • ,
  • James McCracken, M.D.

      Affiliations

    • University of California Los Angeles
    • ,
  • James McGough, M.D.

      Affiliations

    • University of California Los Angeles
    • ,
  • Stanley F. Nelson, M.D.

      Affiliations

    • University of California Los Angeles
    • ,
  • Angela M. Reiersen, M.D.

      Affiliations

    • Washington University School of Medicine, St. Louis, MO
    • ,
  • Timothy E. Wilens, M.D.

      Affiliations

    • Massachusetts General Hospital and Harvard Medical School, Boston, MA
    • ,
  • Janet Wozniak, M.D.

      Affiliations

    • Massachusetts General Hospital and Harvard Medical School, Boston, MA
    • ,
  • Benjamin M. Neale, Ph.D.

      Affiliations

    • Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA
    • ,
  • Stephen V. Faraone, Ph.D.

      Affiliations

    • SUNY Upstate Medical University

,Accepted 22 March 2010.

References 

  1. Mick E, Faraone SV. Genetics of attention deficit hyperactivity disorder. Child Adolesc Psychiatr Clin North Am. 2008;17:261–284
  2. Zhou K, Dempfle A, Arcos-Burgos M, et al. Meta-analysis of genomewide linkage scans of attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:1392–1398
  3. Brookes K, Xu X, Chen W, et al. The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: association signals in DRD4, DAT1 and 16 other genes. Mol Psychiatry. 2006;11:934–953
  4. Lesch KP, Timmesfeld N, Renner TJ, et al. Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies. J Neural Transm. 2008;115:1573–1585
  5. Neale BM, Lasky-Su J, Anney R, et al. Genome-wide association scan of attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:1337–1344
  6. Lasky-Su J, Neale BM, Franke B, et al. Genome-wide association scan of quantitative traits for attention deficit hyperactivity disorder identifies novel associations and confirms candidate gene associations. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:1345–1354
  7. Todd RD, Sitdhiraksa N, Reich W, et al. Discrimination of DSM-IV and latent class attention-deficit/hyperactivity disorder subtypes by educational and cognitive performance in a population-based sample of child and adolescent twins. J Am Acad Child Adolesc Psychiatry. 2002;41:820–828
  8. Neuman RJ, Sitdhiraksa N, Reich W, et al. Estimation of prevalence of DSM-IV and latent class-defined ADHD subtypes in a population-based sample of child and adolescent twins. Twin Res Hum Genet. 2005;8:392–401
  9. Todd RD, Joyner CA, Heath AC, Neuman RJ, Reich W. Reliability and stability of a semistructured DSM-IV interview designed for family studies. J Am Acad Child Adolesc Psychiatry. 2003;42:1460–1468
  10. Smalley SL, McGough JJ, Del'Homme M, et al. Familial clustering of symptoms and disruptive behaviors in multiplex families with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2000;39:1135–1143
  11. Cutler DJ, Zwick ME, Carrasquillo MM, et al. High-throughput variation detection and genotyping using microarrays. Genome Res. 2001;11:1913–1925
  12. Gordon D, Finch SJ, Nothnagel M, Ott J. Power and sample size calculations for case-control genetic association tests when errors are present: application to single nucleotide polymorphisms. Hum Hered. 2002;54:22–33
  13. Hirschhorn JN, Daly MJ. Genome-wide association studies for common diseases and complex traits. Nat Rev Genet. 2005;6:95–108
  14. Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575
  15. Dudbridge F, Gusnanto A. Estimation of significance thresholds for genomewide association scans. Genet Epidemiol. 2008;32:227–234
  16. Pe'er I, Yelensky R, Altshuler D, Daly MJ. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol. 2008;32:381–385
  17. Gizer IR, Ficks C, Waldman ID. Candidate gene studies of ADHD: a meta-analytic review. Hum Genet. 2009;126:51–90
  18. de Silva MG, Elliott K, Dahl HH, et al. Disruption of a novel member of a sodium/hydrogen exchanger family and DOCK3 is associated with an attention deficit hyperactivity disorder-like phenotype. J Med Genet. 2003;40:733–740
  19. Lasky-Su J, Anney RJ, Neale BM, et al. Genome-wide association scan of the time to onset of attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:1355–1358
  20. Faraone SV, Perlis RH, Doyle AE, et al. Molecular genetics of attention deficit hyperactivity disorder. Biol Psychiatry. 2005;57:1313–1323
  21. Levy D, Ehret GB, Rice K, et al. Genome-wide association study of blood pressure and hypertension. Nat Genet. 2009;41:677–687
  22. Newton-Cheh C, Johnson T, Gateva V, et al. Genome-wide association study identifies eight loci associated with blood pressure. Nat Genet. 2009;41:666–676
  23. Faraone SV, Biederman J, Mick E. The age-dependent decline of attention deficit hyperactivity disorder: a meta-analysis of follow-up studies. Psychol Med. 2006;36:159–165
  24. Faraone SV, Biederman J, Monuteaux MC. Toward guidelines for pedigree selection in genetic studies of attention deficit hyperactivity disorder. Genet Epidemiol. 2000;18:1–16
  25. Sonuga-Barke EJ, Lasky-Su J, Neale BM, et al. Does parental expressed emotion moderate genetic effects in ADHD? (An exploration using a genome wide association scan). Am J Med Genet B Neuropsychiatr Genet. 2008;147B:1359–1368
  26. Anney RJ, Lasky-Su J, O'Dushlaine C, et al. Conduct disorder and ADHD: evaluation of conduct problems as a categorical and quantitative trait in the international multicentre ADHD genetics study. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:1369–1378
  27. Elia J, Gai X, Xie HM, et al. Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes [published online ahead of print June 23, 2009]. Mol Psychiatry. doi: 10.1038/mp.2009.57.
  28. Neale BM, Purcell S. The positives, protocols, and perils of genome-wide association. Am J Med Genet B Neuropsychiatr Genet. 2008;147B:1288–1294
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 This article was reviewed under and accepted by Ad Hoc Editor James F. Leckman, M.D.

 Genotyping was conducted by Genizon BioSciences Inc. with the financial support of Pfizer Inc. Subject ascertainment and assessment was supported by the following sources: National Institutes of Health (NIH) grants R13MH059126, R01MH62873, U01MH085518 and R01MH081803 to S.V.Faraone; National Institute of Neurological Disorders and Stroke (NINDS) grant NS054124 S. Loo; National Institute of Mental Health (NIMH) grant MH01966 to J. McGough; National Institute on Drug Abuse (NIDA) grant K24 DA016264 to T. Wilens; NIMH grant MH63706 to S. Smalley; and NIMH grants K08MH001503 and R01MH066237 to J. Wozniak.

 This article is one of several articles published in the August and September issues of the Journal of the American Academy of Child and Adolescent Psychiatry that explores the intersection of genetics and mental health disorders in children and adolescents. The editors invite the reader to investigate the additional articles on this burgeoning area of developmental psychopathology.

 Disclosure: Dr. Mick receives research support from Ortho-McNeil Janssen Scientific Affairs, Pfizer, Shire Pharmaceuticals, and has served on the advisory board 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 (NIMH), and the National Institute of Child Health and Human Development (NICHD). He has served on the speakers' bureau for Fundacion Areces, Medice Pharmaceuticals, and the Spanish Child Psychiatry Association. In previous years, Dr. Biederman 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, NARSAD, National Institute on Drug Abuse (NIDA), New River, Novartis, Noven, Neurosearch, Pfizer, Pharmacia, The Prechter Foundation, Shire, The Stanley Foundation, UCB Pharma, Inc., and Wyeth.

 Dr. McCracken has received research support from Bristol-Myers Squibb, Aspect, and Seaside Pharmaceuticals. He has served as a consultant to Novopharm and BioMarin, and has received speaker honoraria from the Tourette Syndrome Association, Veritas, and CME Outfitters.

 Dr. McGough has served as a consultant to and received research support and consulting honoraria from Eli Lilly and Co. and Shire Pharmaceuticals.

 Dr. Wilens has received grant support from Abbott, McNeil, Eli Lilly and Co., the National Institutes of Health (NIH), the National Institute on Drug Abuse (NIDA), Merck, and Shire. He has served on the speakers' bureaus for Eli Lilly and Co., McNeil, Novartis, and Shire. He has served as a consultant for Abbott, AstraZeneca, McNeil, Eli Lilly and Co., the NIH/NIDA, Novartis, Merck, and Shire. Dr. Wilens receives royalties from Guilford Press for his book, Straight Talk About Psychiatric Medications for Kids.

 Dr. Wozniak receives royalties from Bantam Books for her book, Is Your Child Bipolar? Dr. Wozniak has served on the speakers' bureau for McNeil, Primedia/Massachusetts General Hospital (MGH), Psychiatry Academy, and Eli Lilly and Co. Dr. Wozniak is on the advisory board and has served as a consultant for Pfizer and Shire. She receives research support from McNeil, Shire, and Eli Lilly and Co.

 Dr. Faraone has, in the past year, received consulting fees and has been 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 or has been on Advisory Boards or has 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.

 Drs. Todorov, Smalley, Hu, Loo, Todd (deceased), Dechairo, Nelson, Reiersen, Neale, and Ms. Byrne, and Mr. Guiney report no biomedical financial interests or potential conflicts of interest.

 This article is discussed in an editorial by Drs. James J. Hudziak and Stephen V. Faraone on page 729 of the August 2010 issue.

 Supplemental material cited in this article is available online.

PII: S0890-8567(10)00290-X

doi: 10.1016/j.jaac.2010.02.014

Journal of the American Academy of Child & Adolescent Psychiatry
Volume 49, Issue 9 , Pages 898-905.e3 , September 2010

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