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A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs

Molecular Psychiatry volume 11, pages 196–205 (2006)Cite this article

Abstract

Three groups have previously performed genome scans in attention-deficit/hyperactivity disorder (ADHD); linkage to chromosome 5p13 was detected in all of the respective studies. In the current study, we performed a whole-genome scan with 102 German families with two or more offspring who currently fulfilled the diagnostic criteria for ADHD. Including subsequent fine mapping on chromosome 5p, a total of 523 markers were genotyped. The highest nonparametric multipoint LOD score of 2.59 (empirical genome-wide significance 0.1) was obtained for chromosome 5p at 17 cM (according to the Marshfield map). Subsequent analyses revealed (a) a higher LOD score of 3.37 at 39 cM for a quantitative severity score based on symptoms of inattention than for hyperactivity/impulsivity (LOD score of 1.11 at 59 cM), and (b) an HLOD of 4.75 (empirical genome-wide significance 0.001) based on a parametric model assuming dominant inheritance. The locus of the solute carrier 6A3 (SLC6A3; dopamine transporter 1; DAT1) localizes to 5p15.33; the gene has repeatedly been implicated in the etiology of ADHD. However, in our sample the DAT1 VNTR did not show association with ADHD. We additionally identified nominal evidence for linkage to chromosomes 6q, 7p, 9q, 11 q, 12q and 17p, which had also been identified in previous scans. Despite differences in ethnicity, ascertainment and phenotyping schemes, linkage results in ADHD appear remarkably consistent.

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References

  1. Faraone SV, Biederman J . Neurobiology of attention-deficit hyperactivity disorder. Biol Psychiatry 1998; 44: 951–958.

    Article  CAS  Google Scholar 

  2. Biederman J, Faraone SV, Keenan K, Benjamin J, Krifcher B, Moore C et al. Further evidence for family-genetic risk factors in attention deficit hyperactivity disorder. Patterns of comorbidity in probands and relatives psychiatrically and pediatrically referred samples. Arch Gen Psychiatry 1992; 49: 728–738.

    Article  CAS  Google Scholar 

  3. Heiser P, Friedel S, Dempfle A, Konrad K, Smidt J, Grabarkiewicz J et al. Molecular Genetic Aspects of Attention-Deficit/Hyperactivity Disorder. Neurosci Biobehav Rev 2004; 28: 625–641.

    Article  CAS  Google Scholar 

  4. Faraone SV, Doyle AE . The nature and heritability of attention- deficit/hyperactivity disorder. Child Adolesc Psychiatr Clin N Am 2001; 10: 299–316, viii–ix.

    Article  CAS  Google Scholar 

  5. Maher BS, Marazita ML, Ferrell RE, Vanyukov MM . Dopamine system genes and attention deficit hyperactivity disorder: a meta-analysis. Psychiatr Genet 2002; 12: 207–215.

    Article  Google Scholar 

  6. Purper-Ouakil D, Wohl M, Mouren MC, Verpillat P, Ades J, Gorwood P . Meta- analysis of family-based association studies between the dopamine transporter gene and attention deficit hyperactivity disorder. Psychiatr Genet 2005; 15: 53–59.

    Article  CAS  Google Scholar 

  7. Fisher SE, Francks C, McCracken JT, McGough JJ, Marlow AJ, MacPhie IL et al. A genome-wide 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. Ogdie MN, Fisher SE, Yang M, Ishii J, Francks C, Loo SK et al. Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11. Am J Hum Genet 2004; 75: 661–668.

    Article  CAS  Google Scholar 

  10. Bakker SC, 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. 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 

  12. Lander E, Kruglyak L . dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.

    Article  CAS  Google Scholar 

  13. Smalley SL, Kustanovich V, Minassian SL, Stone JL, Ogdie MN, McGough JJ . Genetic linkage of attention-deficit/hyperactivity disorder on chromosome 16p13, in a region implicated in autism. Am J Hum Genet 2002; 71: 959–963.

    Article  Google Scholar 

  14. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Press: Washington, DC, 1994.

  15. Wechsler D . Examiner's Manual: Wechsler Intelligence Scale for Children-Third Edition. Psychological Corporation: New York, 1991.

    Google Scholar 

  16. Tewes U, Rossmann R, Schallberger U . Der Hamburg-Wechsler-Intelligenztest fuer Kinder (HAWIK-III). Huber-Verlag: Bern, 1999.

    Google Scholar 

  17. Kaufman AS, Kaufman NL . K-ABC: Kaufman – Assessment Battery for Children. AGS Publishing: Minnesota, 1994.

    Google Scholar 

  18. Melchers P, Preuss U . K-ABC: Kaufman – Assessment Battery for Children. Deutsche Bearbeitung. Swets & Zeitlinger: Amsterdam, 1994.

    Google Scholar 

  19. Weiss RH . Grundintelligenztest Skala 2 (CFT 20) mit Wortschatztest (WS) und Zahlenfolgentest (ZF). 4., ueberarbeitete Auflage. Westermann: Braunschweig, 1998.

    Google Scholar 

  20. Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P et al. Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL-D): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 1997; 36: 980–988.

    Article  CAS  Google Scholar 

  21. Delmo C, Weiffenbach O, Gabriel M, Poustka F . 3. Auflage der deutschen Forschungsversion des K-SADS-PL-D, erweitert um ICD-10-Diagnostik. 2002; 22.

  22. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd edn, rev. edn. American Psychiatric Association: Washington, DC, 1987.

  23. World Health Organization. The ICD-10 classification of mental and behavioral disorders: Diagnostic criteria for research. Genf 1993.

  24. Achenbach TM, Edelbrock CS . Psychopathology of childhood. Annu Rev Psychol 1984; 35: 227–256.

    Article  CAS  Google Scholar 

  25. Achenbach TM . Empirically Based Taxonomy: How to Use Syndromes and Profile Types Derived From the CBCL From 4 to 18, TRF, and WSR. Department of Psychiatry, University of Vermont, Burlington, 1993.

    Google Scholar 

  26. Remschmidt H, Walter R . Psychological symptoms in school children. An epidemiologic study. Z Kinder Jugendpsychiatr 1990; 18: 121–132.

    CAS  Google Scholar 

  27. Doepfner M, Lehmkuhl G . Diagnostik-System für psychische Störungen im Kindes- und Jugendalter nach ICD-10 und DSM-IV. Huber: Bern, 1998.

    Google Scholar 

  28. Saar K, Geller F, Ruschendorf F, Reis A, Friedel S, Schauble N et al. Genome scan for childhood and adolescent obesity in German families. Pediatrics 2003; 111: 321–327.

    Article  Google Scholar 

  29. Abecasis GR, Cherny SS, Cookson WO, Cardon LR . GRR: graphical representation of relationship errors. Bioinformatics 2001; 17: 742–743.

    Article  CAS  Google Scholar 

  30. 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 

  31. Mukhopadhyay N, Almasy L, Schroeder M, Mulvihill WP, Weeks DE . Mega2, a data-handling program for facilitating genetic linkage and association analyses. Am J Hum Genet 1999; 65: A43632.

    Google Scholar 

  32. 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 

  33. Abecasis GR, Wigginton JE . Handling marker–marker linkage disequilibrium: pedigree analysis with clustered markers. Am J Hum Genet, in press.

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

    Article  CAS  Google Scholar 

  35. 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 

  36. Sham PC, Purcell S, Cherny SS, Abecasis GR . Powerful regression-based quantitative-trait linkage analysis of general pedigrees. Am J Hum Genet 2002; 71: 238–253.

    Article  CAS  Google Scholar 

  37. Bruehl B, Doepfner M, Lehmkuhl G . Der Fremdbeurteilungsbogen für hyperkinetische Störungen (FBB-HKS) - Prävalenz hyperkinetischer Störungen im Elternurteil und psychometrische Kriterien. Kindheit und Entwicklung 2000; 9: 115–125.

    Google Scholar 

  38. Li C, Scott LJ, Boehnke M . Assessing whether an allele can account in part for a linkage signal: the genotype-IBD sharing test (GIST). Am J Hum Genet 2004; 74: 418–431.

    Article  CAS  Google Scholar 

  39. Martin ER, Monks SA, Warren LL, Kaplan NL . A test for linkage and association in general pedigrees: the pedigree disequilibrium test. Am J Hum Genet 2000; 67: 146–154.

    Article  CAS  Google Scholar 

  40. Cordell HJ . Sample size requirements to control for stochastic variation in magnitude and location of allele-sharing linkage statistics in affected sibling pairs. Ann Hum Genet 2001; 65: 491–502.

    Article  CAS  Google Scholar 

  41. Spencer T, Biederman J, Wilens T . Pharmacotherapy of attention deficit hyperactivity disorder. Child Adolesc Psychiatric Clin North Am 2000; 9: 77–97.

    Article  CAS  Google Scholar 

  42. Dougherty DD, Bonab AA, Spencer TJ, Rauch SL, Madras BK, Fischman AJ . Dopamine transporter density in patients with attention deficit hyperactivity disorder. Lancet 1999; 354: 2132–2133.

    Article  CAS  Google Scholar 

  43. Krause KH, Dresel SH, Krause J, Kung HF, Tatsch K . Increased striatal dopamine transporter in adult patients with attention deficit hyperactivity disorder: effects of methylphenidate as measured by single photon emissioncomputed tomography. Neurosci Lett 2000; 285: 107–110.

    Article  CAS  Google Scholar 

  44. Vles JS, Feron FJ, Hendriksen JG, Jolles J, van Kroonenburgh MJ, Weber WE . Methylphenidate down-regulates the dopamine receptor and transporter system in children with attention deficit hyperkinetic disorder (ADHD). Neuropediatrics 2003; 34: 77–80.

    Article  CAS  Google Scholar 

  45. Mill J, Asherson P, Craig I, D'Souza U . Transient expression of allelic variants of a VNTR in the dopamine transporter gene (DAT1). BMC Genetics 2005; 6: 3.

    Article  Google Scholar 

  46. 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 

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Acknowledgements

We thank the families for their participation in this study. Seven physicians ascertained the families and performed the phenotypical assessments; we greatly acknowledge their substantial contribution to this study. We thank Regina Pospiech and Inka Szangolies for excellent technical assistance and Gundula Ringler for exceptional data management. The German Ministry for Education and Research (National Genome Research Net; grants 01GS0118, 01GS0482, 01GS0483, 01GR0460) and the Deutsche Forschungsgemeinschaft (grant SCHA 542/10-2) financially supported this study.

Author information

Authors and Affiliations

  1. Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany

    J Hebebrand, S Friedel & A Hinney

  2. Institute of Medical Biometry and Epidemiology, University of Marburg, Marburg, Germany

    A Dempfle & H Schäfer

  3. Molecular Genetics and Gene Mapping Center, Max Delbrück Center Berlin-Buch, Berlin, Germany

    K Saar

  4. Cologne Center for Genomics, University of Cologne, Cologne, Germany

    H Thiele & P Nürnberg

  5. Department of Child and Adolescent Psychiatry, RWTH Aachen, Aachen, Germany

    B Herpertz-Dahlmann & K Konrad

  6. Psychiatric Clinic for Children and Adolescents, Regensburg, Germany

    M Linder & H Kiefl

  7. Department of Child and Adolescent Psychiatry, University of Marburg, Marburg, Germany

    H Remschmidt

  8. Department of Child and Adolescent Psychiatry, University of Würzburg, Würzburg, Germany

    U Hemminger & A Warnke

  9. Department of Child and Adolescent Psychiatry, University of Lübeck, Lübeck, Germany

    U Knölker

  10. Department of Psychiatry, University of Marburg, Marburg, Germany

    P Heiser

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  1. J Hebebrand
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Correspondence to J Hebebrand.

Additional information

Electronic-Database Information

The URLs for data presented herein are as follows: Mega2 version 3.0: http://watson.hgen.pitt.edu

Marshfield map: http://research.marshfieldclinic.org

Golden Path (hg17): http://genome.ucsc.edu

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Hebebrand, J., Dempfle, A., Saar, K. et al. A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs. Mol Psychiatry 11, 196–205 (2006). https://doi.org/10.1038/sj.mp.4001761

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