Home LiteratureArticle Details
PMID: 20732627 Published · ppublish English Journal Article Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Case-control genome-wide association study of attention-deficit/hyperactivity disorder.

Journal of the American Academy of Child and Adolescent Psychiatry ·Vol. 49 ·No. 9 ·2010-09-00 ·Pages 906-20

Neale BM, Medland S, Ripke S, Anney RJ, Asherson P, Buitelaar J, Franke B, Gill M, Kent L, Holmans P, Middleton F, Thapar A, Lesch KP, Faraone SV, Daly M, Nguyen TT, Schäfer H, Steinhausen HC, Reif A, Renner TJ, Romanos M, Romanos J, Warnke A, Walitza S, Freitag C, Meyer J, Palmason H, Rothenberger A, Hawi Z, Sergeant J, Roeyers H, Mick E, Biederman J, IMAGE II Consortium Group

Abstract

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. Thus additional genomewide association studies (GWAS) are needed. We used case-control analyses of 896 cases with DSM-IV ADHD genotyped using the Affymetrix 5.0 array and 2,455 repository controls screened for psychotic and bipolar symptoms genotyped using Affymetrix 6.0 arrays. A consensus SNP set was imputed using BEAGLE 3.0, resulting in an analysis dataset of 1,033,244 SNPs. Data were analyzed using a generalized linear model. No genome-wide significant associations were found. The most significant results implicated the following genes: PRKG1, FLNC, TCERG1L, PPM1H, NXPH1, PPM1H, CDH13, HK1, and HKDC1. The current analyses are a useful addition to the present literature and will make a valuable contribution to future meta-analyses. The candidate gene findings are consistent with a prior meta-analysis in suggesting that the effects of ADHD risk variants must, individually, be very small and/or include multiple rare alleles.

MeSH Terms
Adolescent Attention Deficit Disorder with Hyperactivity/diagnosis,genetics,psychology Case-Control Studies Child Comorbidity Diseases in Twins/diagnosis,genetics,psychology Female Genetic Association Studies Genetic Predisposition to Disease/genetics Genetic Variation Genome-Wide Association Study Genotype Humans Male Polymorphism, Single Nucleotide/genetics
Authors & Affiliations
34 authors, click to expand affiliations / ORCID
Neale Benjamin M
Center for Human Genetic Research, Massachusettes General Hospital, Boston, MA, USA.
Medland Sarah
Ripke Stephan
Anney Richard J L
Asherson Philip
Buitelaar Jan
Franke Barbara
Gill Michael
Kent Lindsey
Holmans Peter
Middleton Frank
Thapar Anita
Lesch Klaus-Peter
Faraone Stephen V
Daly Mark
Nguyen Thuy Trang
Schäfer Helmut
Steinhausen Hans-Christoph
Reif Andreas
Renner Tobias J
Romanos Marcel
Romanos Jasmin
Warnke Andreas
Walitza Susanne
Freitag Christine
Meyer Jobst
Palmason Haukur
Rothenberger Aribert
Hawi Ziarih
Sergeant Joseph
Roeyers Herbert
Mick Eric
Biederman Joseph
IMAGE II Consortium Group
Investigators
50 investigators, click to expand
Neale Benjamin M
Medland Sarah
Ripke Stephan
Anney Richard J L
Asherson Philip
Buitelaar Jan
Gill Michael
Kent Lindsey
Holmans Peter
Middleton Frank
Thapar Anita
Lesch Klaus-Peter
Faraone Stephen V
Ripke Stephan
Medland Sarah
Anney Richard J L
Daly Mark
Nguyen Thuy Trang
Schäfer Helmut
Neale Benjamin M
Middleton Frank
Steinhausen Hans-Christoph
Lesch Klaus-Peter
Reif Andreas
Renner Tobias J
Romanos Marcel
Romanos Jasmin
Warnke Andreas
Walitza Susanne
Nguyen Thuy Trang
Schäfer Helmut
Freitag Christine
Meyer Jobst
Palmason Haukur
Rothenberger Aribert
Buitelaar Jan
Franke Barbara
Gill Michael
Anney Richard J L
Hawi Ziarih
Thapar Anita
Kent Lindsey
Sergeant Joseph
Roeyers Herbert
Asherson Philip
Mick Eric
Faraone Stephen V
Biederman Joseph
Faraone Stephen V
Neale Benjamin M
References (59)
59 references, click to expand
  1. Molecular genetics of attention-deficit/hyperactivity disorder.
    Biol Psychiatry. 2005 Jun 1;57(11):1313-23 PMID: 15950004
  2. A high-density single-nucleotide polymorphism screen of 23 candidate genes in attention deficit hyperactivity disorder: suggesting multiple susceptibility genes among Chinese Han population.
    Mol Psychiatry. 2009 May;14(5):546-54 PMID: 18180757
  3. Genome-wide association scan of the time to onset of attention deficit hyperactivity disorder.
    Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1355-8 PMID: 18937294
  4. Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering.
    Am J Hum Genet. 2007 Nov;81(5):1084-97 PMID: 17924348
  5. Genome-wide association studies provide new insights into type 2 diabetes aetiology.
    Nat Rev Genet. 2007 Sep;8(9):657-62 PMID: 17703236
  6. The worldwide prevalence of ADHD: is it an American condition?
    World Psychiatry. 2003 Jun;2(2):104-13 PMID: 16946911
  7. Structural variation of chromosomes in autism spectrum disorder.
    Am J Hum Genet. 2008 Feb;82(2):477-88 PMID: 18252227
  8. Effect of stimulants on height and weight: a review of the literature.
    J Am Acad Child Adolesc Psychiatry. 2008 Sep;47(9):994-1009 PMID: 18580502
  9. A unified approach to genotype imputation and haplotype-phase inference for large data sets of trios and unrelated individuals.
    Am J Hum Genet. 2009 Feb;84(2):210-23 PMID: 19200528
  10. Linkage to chromosome 1p36 for attention-deficit/hyperactivity disorder traits in school and home settings.
    Biol Psychiatry. 2008 Oct 1;64(7):571-6 PMID: 18439570
  11. Haplotypic analysis of Wellcome Trust Case Control Consortium data.
    Hum Genet. 2008 Apr;123(3):273-80 PMID: 18224336
  12. Characterization of an inversion on the long arm of chromosome 10 juxtaposing D10S170 and RET and creating the oncogenic sequence RET/PTC.
    Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1616-20 PMID: 1542652
  13. The International HapMap Project Web site.
    Genome Res. 2005 Nov;15(11):1592-3 PMID: 16251469
  14. Molecular genetics of attention deficit hyperactivity disorder.
    Psychiatr Clin North Am. 2010 Mar;33(1):159-80 PMID: 20159345
  15. The psychiatric status of the legal families of adopted hyperactive children.
    Arch Gen Psychiatry. 1973 Jun;28(6):888-91 PMID: 4707995
  16. Review of pediatric attention deficit/hyperactivity disorder for the general psychiatrist.
    Psychiatr Clin North Am. 2009 Mar;32(1):39-56 PMID: 19248915
  17. Genome-wide association for methamphetamine dependence: convergent results from 2 samples.
    Arch Gen Psychiatry. 2008 Mar;65(3):345-55 PMID: 18316681
  18. The endophenotype concept in psychiatric genetics.
    Psychol Med. 2007 Feb;37(2):163-80 PMID: 16978446
  19. Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.
    Nat Genet. 2008 May;40(5):638-45 PMID: 18372903
  20. Hippocampal cGMP-dependent protein kinase I supports an age- and protein synthesis-dependent component of long-term potentiation but is not essential for spatial reference and contextual memory.
    J Neurosci. 2003 Jul 9;23(14):6005-12 PMID: 12853418
  21. 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 Oct;11(10):934-53 PMID: 16894395
  22. Predictors of persistence and remission of ADHD into adolescence: results from a four-year prospective follow-up study.
    J Am Acad Child Adolesc Psychiatry. 1996 Mar;35(3):343-51 PMID: 8714323
  23. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants.
    Genet Epidemiol. 2008 May;32(4):381-5 PMID: 18348202
  24. Environmental risk factors for attention-deficit hyperactivity disorder.
    Acta Paediatr. 2007 Sep;96(9):1269-74 PMID: 17718779
  25. 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 Dec 5;147B(8):1345-54 PMID: 18821565
  26. Adoptive and biological families of children and adolescents with ADHD.
    J Am Acad Child Adolesc Psychiatry. 2000 Nov;39(11):1432-7 PMID: 11068899
  27. Estimation of significance thresholds for genomewide association scans.
    Genet Epidemiol. 2008 Apr;32(3):227-34 PMID: 18300295
  28. A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16.
    Mol Psychiatry. 2008 May;13(5):514-21 PMID: 18180756
  29. Deriving phenotypes for molecular genetic studies of substance use disorders: a family study approach.
    Drug Alcohol Depend. 2007 May 11;88(2-3):244-50 PMID: 17141426
  30. What is the prevalence of adult ADHD? Results of a population screen of 966 adults.
    J Atten Disord. 2005 Nov;9(2):384-91 PMID: 16371661
  31. Familial transmission of derived phenotypes for molecular genetic studies of substance use disorders.
    Drug Alcohol Depend. 2008 Jan 1;92(1-3):100-7 PMID: 17766060
  32. Genetics of hyperactivity.
    J Child Psychol Psychiatry. 1975 Jul;16(3):261-4 PMID: 1171894
  33. Dopamine and cAMP-regulated phosphoprotein 32 kDa controls both striatal long-term depression and long-term potentiation, opposing forms of synaptic plasticity.
    J Neurosci. 2000 Nov 15;20(22):8443-51 PMID: 11069952
  34. Candidate gene studies of ADHD: a meta-analytic review.
    Hum Genet. 2009 Jul;126(1):51-90 PMID: 19506906
  35. Candidate genes and neuropsychological phenotypes in children with ADHD: review of association studies.
    J Psychiatry Neurosci. 2009 Mar;34(2):88-101 PMID: 19270759
  36. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis.
    Nat Genet. 2007 May;39(5):596-604 PMID: 17435756
  37. Diagnosing adult attention deficit hyperactivity disorder: are late onset and subthreshold diagnoses valid?
    Am J Psychiatry. 2006 Oct;163(10):1720-9; quiz 1859 PMID: 17012682
  38. Association between microdeletion and microduplication at 16p11.2 and autism.
    N Engl J Med. 2008 Feb 14;358(7):667-75 PMID: 18184952
  39. Attention-deficit hyperactivity disorder.
    Lancet. 2005 Jul 16-22;366(9481):237-48 PMID: 16023516
  40. Common variants on chromosome 6p22.1 are associated with schizophrenia.
    Nature. 2009 Aug 6;460(7256):753-7 PMID: 19571809
  41. Neutrophil dysfunction in guanosine 3',5'-cyclic monophosphate-dependent protein kinase I-deficient mice.
    J Immunol. 2005 Aug 1;175(3):1919-29 PMID: 16034136
  42. Guilt beyond a reasonable doubt.
    Nat Genet. 2007 Jul;39(7):813-5 PMID: 17597768
  43. Phenotypic and measurement influences on heritability estimates in childhood ADHD.
    Eur Child Adolesc Psychiatry. 2010 Mar;19(3):311-23 PMID: 20213230
  44. PLINK: a tool set for whole-genome association and population-based linkage analyses.
    Am J Hum Genet. 2007 Sep;81(3):559-75 PMID: 17701901
  45. Molecular genetics of adult ADHD: converging evidence from genome-wide association and extended pedigree linkage studies.
    J Neural Transm (Vienna). 2008 Nov;115(11):1573-85 PMID: 18839057
  46. Linkage analysis of attention deficit hyperactivity disorder.
    Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1387-91 PMID: 18081027
  47. Identification of loci associated with schizophrenia by genome-wide association and follow-up.
    Nat Genet. 2008 Sep;40(9):1053-5 PMID: 18677311
  48. Large recurrent microdeletions associated with schizophrenia.
    Nature. 2008 Sep 11;455(7210):232-6 PMID: 18668039
  49. Recurrent 16p11.2 microdeletions in autism.
    Hum Mol Genet. 2008 Feb 15;17(4):628-38 PMID: 18156158
  50. Partial replication of a DRD4 association in ADHD individuals using a statistically derived quantitative trait for ADHD in a family-based association test.
    Biol Psychiatry. 2007 Nov 1;62(9):985-90 PMID: 17560555
  51. Rare variants create synthetic genome-wide associations.
    PLoS Biol. 2010 Jan 26;8(1):e1000294 PMID: 20126254
  52. The International HapMap Project.
    Nature. 2003 Dec 18;426(6968):789-96 PMID: 14685227
  53. Abnormal neocortical development in mice lacking cGMP-dependent protein kinase I.
    Brain Res Dev Brain Res. 2005 Nov 7;160(1):1-8 PMID: 16154207
  54. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs.
    Nat Genet. 2008 Oct;40(10):1253-60 PMID: 18776909
  55. Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder.
    Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1392-8 PMID: 18988193
  56. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication.
    Am J Psychiatry. 2006 Apr;163(4):716-23 PMID: 16585449
  57. Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.
    Nat Genet. 2008 Sep;40(9):1056-8 PMID: 18711365
  58. Systematic chart review of the pharmacologic treatment of comorbid attention deficit hyperactivity disorder in youth with bipolar disorder.
    J Child Adolesc Psychopharmacol. 1999;9(4):247-56 PMID: 10630454
  59. Genome-wide association scan of attention deficit hyperactivity disorder.
    Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1337-44 PMID: 18980221
Article Info
Journal
Journal of the American Academy of Child and Adolescent Psychiatry
Abbr.
J Am Acad Child Adolesc Psychiatry
ISSN
1527-5418
Published
2010-09-00
Epub
2010-00-05
Pages
906-20
Language
English
Region
United States
NLM ID
8704565
PMCID
PMC2928577
Subset
IM
Grants
NIMH NIH HHS · U01 MH085518 · United States
NIMH NIH HHS · R01 MH062873 · United States
Wellcome Trust · United Kingdom
NIMH NIH HHS · R01 MH062873-03 · United States
NIMH NIH HHS · R01 MH062873-05S1 · United States
NIMH NIH HHS · R01MH62873 · United States
NIMH NIH HHS · R01MH081803 · United States
NIMH NIH HHS · R01 MH062873-05 · United States
NIMH NIH HHS · R13 MH059126-10 · United States
NIMH NIH HHS · U01 MH085518-01 · United States
Medical Research Council · G0801418 · United Kingdom
NIMH NIH HHS · R01 MH062873-04 · United States
NIMH NIH HHS · R01 MH081803-01 · United States
NIMH NIH HHS · R13 MH059126 · United States
NIMH NIH HHS · R13MH059126 · United States
NIMH NIH HHS · U01MH085518 · United States
NIMH NIH HHS · R01 MH081803 · United States
NIMH NIH HHS · R01 MH062873-01A1 · United States
NIMH NIH HHS · R01 MH062873-02 · United States
Corrections
CommentIn
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]