Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16

Molecular Psychiatry volume 13, pages 514–521 (2008)Cite this article

Abstract

As part of the International Multi-centre ADHD Genetics project we completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type attention deficit hyperactivity disorder (ADHD) proband–sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. We found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (log of the odds, LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, ∼95 cM) and Dutch (LOD>1, ∼100 cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13); both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM; German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Brookes K, Xu X, Chen W, Zhou K, Neale B, Lowe N 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; 10: 934–953.

    Article  Google Scholar 

  2. 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.

    Article  CAS  Google Scholar 

  3. Smalley SL . Genetic influences in childhood-onset psychiatric disorders: autism and attention-deficit/hyperactivity disorder. Am J Hum Genet 1997; 60: 1276–1282.

    Article  CAS  Google Scholar 

  4. Faraone SV, Perlis RH, Doyle AE, Smoller JW, Goralnick JJ, Holmgren MA et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 2005; 57: 1313–1323.

    Article  CAS  Google Scholar 

  5. Li D, Sham PC, Owen MJ, He L . Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Hum Mol Genet 2006; 15: 2276–2284.

    Article  CAS  Google Scholar 

  6. Kuntsi J, Neale BM, Chen W, Faraone SV, Asherson P . The IMAGE project: methodological issues for the molecular genetic analysis of ADHD. Behav Brain Funct 2006; 2: 27.

    Article  Google Scholar 

  7. Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ, MacPhie IL et al. A genomewide scan for loci involved in attention-deficit/hyperactivity disorder. Am J Hum Genet 2002; 70: 1183–1196.

    Article  CAS  Google Scholar 

  8. Ogdie MN, Macphie IL, Minassian SL, Yang M, Fisher SE, Francks C et al. A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11. Am J Hum Genet 2003; 72: 1268–1279.

    Article  CAS  Google Scholar 

  9. Faraone SV, Doyle AE, Lasky-Su J, Sklar PB, D'Angelo E, Gonzalez-Heydrich J et al. Linkage analysis of attention deficit hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet 2007; e-pub ahead of print 14 December 2007.

  10. Bakker SC, van der Meulen EM, Buitelaar JK, Sandkuijl LA, Pauls DL, Monsuur AJ et al. A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. Am J Hum Genet 2003; 72: 1251–1260.

    Article  CAS  Google Scholar 

  11. Hebebrand J, Dempfle A, Saar K, Thiele H, Herpertz-Dahlmann B, Linder M et al. A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs. Mol Psychiatry 2006; 11: 196–205.

    Article  CAS  Google Scholar 

  12. Arcos-Burgos M, Castellanos FX, Pineda D, Lopera F, Palacio JD, Palacio LG et al. Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11. Am J Hum Genet 2004; 75: 998–1014.

    Article  CAS  Google Scholar 

  13. Friedel S, Saar K, Sauer S, Dempfle A, Walitza S, Renner T et al. Association and linkage of allelic variants of the dopamine transporter gene in ADHD. Mol Psychiatry 2007; 12: 923–933.

    Article  CAS  Google Scholar 

  14. Neale BM, Sham PC, Purcell S, Banaschewski T, Buitelaar J, Franke B et al. Population differences in the International Multi-centre ADHD Gene Project. Genet Epidemiol 2007; e-pub ahead of print 14 September 2007.

  15. Taylor E, Everitt B, Thorley G, Schachar R, Rutter M, Wieselberg M . Conduct disorder and hyperactivity: II. A cluster analytic approach to the identification of a behavioural syndrome. Br J Psychiatry 1986; 149: 768–777.

    Article  CAS  Google Scholar 

  16. Taylor E, Schachar R, Thorley G, Wieselberg HM, Everitt B, Rutter M . Which boys respond to stimulant medication? A controlled trial of methylphenidate in boys with disruptive behaviour. Psychol Med 1987; 17: 121–143.

    Article  CAS  Google Scholar 

  17. Taylor E, Schachar R, Thorley G, Wieselberg M . Conduct disorder and hyperactivity: I. Separation of hyperactivity and antisocial conduct in British child psychiatric patients. Br J Psychiatry 1986; 149: 760–767.

    Article  CAS  Google Scholar 

  18. Conners CK . Conners' Rating Scales-Revised, 6th edn. MHS: Toronto, 2003.

    Google Scholar 

  19. Goodman R . The strengths and difficulties questionnaire: a research note. J Child Psychol Psychiatry 1997; 38: 581–586.

    Article  CAS  Google Scholar 

  20. Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B et al. A high-resolution recombination map of the human genome. Nat Genet 2002; 31: 241–247.

    Article  CAS  Google Scholar 

  21. Epstein MP, Duren WL, Boehnke M . Improved inference of relationship for pairs of individuals. Am J Hum Genet 2000; 67: 1219–1231.

    Article  CAS  Google Scholar 

  22. O'Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.

    Article  CAS  Google Scholar 

  23. Wigginton JE, Abecasis GR . PEDSTATS: descriptive statistics, graphics and quality assessment for gene mapping data. Bioinformatics 2005; 21: 3445–3447.

    Article  CAS  Google Scholar 

  24. Abecasis GR, Cherny SS, Cookson WO, Cardon LR . Merlin—rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 2002; 30: 97–101.

    Article  CAS  Google Scholar 

  25. Kong A, Cox NJ . Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 1997; 61: 1179–1188.

    Article  CAS  Google Scholar 

  26. Whittemore AS, Halpern J . A class of tests for linkage using affected pedigree members. Biometrics 1994; 50: 118–127.

    Article  CAS  Google Scholar 

  27. Huang Q, Shete S, Amos CI . Ignoring linkage disequilibrium among tightly linked markers induces false-positive evidence of linkage for affected sib pair analysis. Am J Hum Genet 2004; 75: 1106–1112.

    Article  CAS  Google Scholar 

  28. Abecasis GR, Wigginton JE . Handling marker–marker linkage disequilibrium: pedigree analysis with clustered markers. Am J Hum Genet 2005; 77: 754–767.

    Article  CAS  Google Scholar 

  29. Levinson DF, Holmans P . The effect of linkage disequilibrium on linkage analysis of incomplete pedigrees. BMC Genet 2005; 6(Suppl 1): S6.

    Article  Google Scholar 

  30. Leal SM, Ott J . Effects of stratification in the analysis of affected-sib-pair data: benefits and costs. Am J Hum Genet 2000; 66: 567–575.

    Article  CAS  Google Scholar 

  31. Ogdie MN, Bakker SC, Fisher SE, Francks C, Yang MH, Cantor RM et al. Pooled genome-wide linkage data on 424 ADHD ASPs suggests genetic heterogeneity and a common risk locus at 5p13. Mol Psychiatry 2006; 11: 5–8.

    Article  CAS  Google Scholar 

  32. Bobb AJ, Addington AM, Sidransky E, Gornick MC, Lerch JP, Greenstein DK et al. Support for association between ADHD and two candidate genes: NET1 and DRD1. Am J Med Genet B Neuropsychiatr Genet 2005; 134: 67–72.

    Article  Google Scholar 

  33. Xu X, Knight J, Brookes K, Mill J, Sham P, Craig I et al. DNA pooling analysis of 21 norepinephrine transporter gene SNPs with attention deficit hyperactivity disorder: no evidence for association. Am J Med Genet B Neuropsychiatr Genet 2005; 134: 115–118.

    Article  Google Scholar 

  34. Risch N . Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genet Epidemiol 1990; 7: 3–16.

    Article  CAS  Google Scholar 

  35. Risch N, Merikangas K . The future of genetic studies of complex human diseases. Science 1996; 273: 1516–1517.

    Article  CAS  Google Scholar 

  36. Faraone SV, Biederman J, Mennin D, Russell R, Tsuang MT . Familial subtypes of attention deficit hyperactivity disorder: a 4-year follow-up study of children from antisocial-ADHD families. J Child Psychol Psychiatry 1998; 39: 1045–1053.

    Article  CAS  Google Scholar 

  37. Lowe N, Kirley A, Hawi Z, Sham P, Wickham H, Kratochvil CJ et al. Joint analysis of the DRD5 marker concludes association with attention-deficit/hyperactivity disorder confined to the predominantly inattentive and combined subtypes. Am J Hum Genet 2004; 74: 348–356.

    Article  CAS  Google Scholar 

  38. Waldman ID, Rowe DC, Abramowitz A, Kozel ST, Mohr JH, Sherman SL et al. Association and linkage of the dopamine transporter gene and attention-deficit hyperactivity disorder in children: heterogeneity owing to diagnostic subtype and severity. Am J Hum Genet 1998; 63: 1767–1776.

    Article  CAS  Google Scholar 

  39. Rasmussen ER, Neuman RJ, Heath AC, Levy F, Hay DA, Todd RD . Familial clustering of latent class and DSM-IV defined attention-deficit/hyperactivity disorder (ADHD) subtypes. J Child Psychol Psychiatry 2004; 45: 589–598.

    Article  Google Scholar 

  40. Todd RD, Rasmussen ER, Neuman RJ, Reich W, Hudziak JJ, Bucholz KK et al. Familiality and heritability of subtypes of attention deficit hyperactivity disorder in a population sample of adolescent female twins. Am J Psychiatry 2001; 158: 1891–1898.

    Article  CAS  Google Scholar 

  41. Hirschhorn JN, Daly MJ . Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 2005; 6: 95–108.

    Article  CAS  Google Scholar 

  42. Wang WY, Barratt BJ, Clayton DG, Todd JA . Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 2005; 6: 109–118.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The IMAGE project is a multi-site, international effort supported by NIH grant R01MH62873 to SV Faraone. Site Principal Investigators are Philip Asherson, Tobias Banaschewski, Jan Buitelaar, Richard P Ebstein, Stephen V Faraone, Michael Gill, Ana Miranda, Robert D Oades, Herbert Roeyers, Aribert Rothenberger, Joseph Sergeant, Edmund Sonuga-Barke and Hans-Christoph Steinhausen; Senior co-investigators are Ian Craig, Peter McGuffin, Robert Plomin, Pak Sham, Eric Taylor, Iris Manor, Jacques Eisenberg and Margaret Thompson. Chief Investigators are Evi Bitsakou, Cathelijne Buschgens, Wai Chen, Hanna Christiansen, Barbara Franke, Rafaela Marco, U Mueller, Fernando Mulas, Lamprini Psychogiou, Nanda Rommelse, Aisling Mulligan and Henrik Uebel. Other investigators are Marieke Altink, Frits Boer, Alysa Doyle, Ellen Fliers, Alexander Heise, Jo Knight and Ruud Minderaa. We thank all the families who kindly participated in this research.

Author information

Author notes

  1. P Asherson and K Zhou: Shared first authorship.

Authors and Affiliations

  1. Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK

    P Asherson, K Zhou, K Brookes, D Cambell, W Chen, K Fleischman, R Howe-Forbes, L Johansson, B Neale, F Rijsdijk, V Sethna, X Xu & E Taylor

  2. Department of Psychiatry, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland

    R J L Anney, M Gill, L Butler & J Sorohan

  3. Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    B Franke & A Mulligan

  4. Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

    B Franke, J Buitelaar, M Altink, C Buschgens & E Fliers

  5. ADHD Clinic, Geha Mental Health Center, Petak Tikvah, Israel

    R Ebstein, L Feldman, A Goldfarb, S Medad, K Rabin, J Eisenberg & I Manor

  6. Triversum, Alkmaar, Holland

    R Arnold

  7. Amsterdam Medical Centre de Bascule, Amsterdam, Holland

    F Boer

  8. University Clinic for Child and Adolescent Psychiatry, Essen, Germany

    H Christiansen & R D Oades

  9. Child and Adolescent Psychiatry, University of G,

    A Heise, H Uebel, T Banaschewski & A Rothenberger

  10. ö,

    A Heise, H Uebel, T Banaschewski & A Rothenberger

  11. ttingen, G, ö, ttingen, Germany

    A Heise, H Uebel, T Banaschewski & A Rothenberger

  12. Department of Experimental Clinical Health Psychology, Ghent University, Ghent, Belgium

    I Gabriëls & H Roeyers

  13. Shaare Zedek Medical Center, Jerusalem, Israel

    I Lubetzki

  14. Department of Developmental and Educational Psychology, University of Valencia, Valencia, Spain

    R Marco, F Mulas & A Miranda

  15. University Centre for Child and Adolescence Psychiatry, University Medical Centre, Groningen, The Netherlands

    R Minderaa

  16. Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland

    U Müller & H-C Steinhausen

  17. Vrije Universiteit, Amsterdam, Holland

    N Rommelse & J Sergeant

  18. School of Psychology, University of Southampton, Highfield, Southampton, UK

    L Psychogiou, A Weeks, R Barrett, E Sonuga-Barke & M Thompson

  19. Department of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA

    S V Faraone

Authors
  1. P Asherson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R J L Anney
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B Franke
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Buitelaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R Ebstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Gill
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. M Altink
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. R Arnold
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. F Boer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. K Brookes
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. C Buschgens
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. L Butler
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. D Cambell
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. W Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. H Christiansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. L Feldman
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. K Fleischman
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. E Fliers
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. R Howe-Forbes
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. A Goldfarb
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. A Heise
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. I Gabriëls
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. L Johansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. I Lubetzki
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. R Marco
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. S Medad
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. R Minderaa
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. F Mulas
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. U Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. A Mulligan
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. B Neale
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. F Rijsdijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. K Rabin
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. N Rommelse
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. V Sethna
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. J Sorohan
    View author publications

    You can also search for this author in PubMed Google Scholar

  38. H Uebel
    View author publications

    You can also search for this author in PubMed Google Scholar

  39. L Psychogiou
    View author publications

    You can also search for this author in PubMed Google Scholar

  40. A Weeks
    View author publications

    You can also search for this author in PubMed Google Scholar

  41. R Barrett
    View author publications

    You can also search for this author in PubMed Google Scholar

  42. X Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  43. T Banaschewski
    View author publications

    You can also search for this author in PubMed Google Scholar

  44. E Sonuga-Barke
    View author publications

    You can also search for this author in PubMed Google Scholar

  45. J Eisenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  46. I Manor
    View author publications

    You can also search for this author in PubMed Google Scholar

  47. A Miranda
    View author publications

    You can also search for this author in PubMed Google Scholar

  48. R D Oades
    View author publications

    You can also search for this author in PubMed Google Scholar

  49. H Roeyers
    View author publications

    You can also search for this author in PubMed Google Scholar

  50. A Rothenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  51. J Sergeant
    View author publications

    You can also search for this author in PubMed Google Scholar

  52. H-C Steinhausen
    View author publications

    You can also search for this author in PubMed Google Scholar

  53. E Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  54. M Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  55. S V Faraone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Asherson.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Asherson, P., Zhou, K., Anney, R. et al. A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16. Mol Psychiatry 13, 514–521 (2008). https://doi.org/10.1038/sj.mp.4002140

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4002140

Keywords

This article is cited by

Search

Advanced search

Quick links