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
Faraone SV, Biederman J . Neurobiology of attention-deficit hyperactivity disorder. Biol Psychiatry 1998; 44: 951–958.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Lander E, Kruglyak L . dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 1995; 11: 241–247.
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.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. American Psychiatric Press: Washington, DC, 1994.
Wechsler D . Examiner's Manual: Wechsler Intelligence Scale for Children-Third Edition. Psychological Corporation: New York, 1991.
Tewes U, Rossmann R, Schallberger U . Der Hamburg-Wechsler-Intelligenztest fuer Kinder (HAWIK-III). Huber-Verlag: Bern, 1999.
Kaufman AS, Kaufman NL . K-ABC: Kaufman – Assessment Battery for Children. AGS Publishing: Minnesota, 1994.
Melchers P, Preuss U . K-ABC: Kaufman – Assessment Battery for Children. Deutsche Bearbeitung. Swets & Zeitlinger: Amsterdam, 1994.
Weiss RH . Grundintelligenztest Skala 2 (CFT 20) mit Wortschatztest (WS) und Zahlenfolgentest (ZF). 4., ueberarbeitete Auflage. Westermann: Braunschweig, 1998.
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.
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.
American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 3rd edn, rev. edn. American Psychiatric Association: Washington, DC, 1987.
World Health Organization. The ICD-10 classification of mental and behavioral disorders: Diagnostic criteria for research. Genf 1993.
Achenbach TM, Edelbrock CS . Psychopathology of childhood. Annu Rev Psychol 1984; 35: 227–256.
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.
Remschmidt H, Walter R . Psychological symptoms in school children. An epidemiologic study. Z Kinder Jugendpsychiatr 1990; 18: 121–132.
Doepfner M, Lehmkuhl G . Diagnostik-System für psychische Störungen im Kindes- und Jugendalter nach ICD-10 und DSM-IV. Huber: Bern, 1998.
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.
Abecasis GR, Cherny SS, Cookson WO, Cardon LR . GRR: graphical representation of relationship errors. Bioinformatics 2001; 17: 742–743.
O'Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.
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.
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.
Abecasis GR, Wigginton JE . Handling marker–marker linkage disequilibrium: pedigree analysis with clustered markers. Am J Hum Genet, in press.
Whittemore AS, Halpern J . A class of tests for linkage using affected pedigree members. Biometrics 1994; 50: 118–127.
Kong A, Cox NJ . Allele-sharing models: LOD scores and accurate linkage tests. Am J Hum Genet 1997; 61: 1179–1188.
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.
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.
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.
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.
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.
Spencer T, Biederman J, Wilens T . Pharmacotherapy of attention deficit hyperactivity disorder. Child Adolesc Psychiatric Clin North Am 2000; 9: 77–97.
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.
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.
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.
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.
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.
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.
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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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DOI: https://doi.org/10.1038/sj.mp.4001761
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