Abstract
Previously, we had reported a genome-wide scan for attention-deficit/hyperactivity disorder (ADHD) in 102 families with affected sibs of German ancestry; the highest multipoint LOD score of 4.75 was obtained on chromosome 5p13 (parametric HLOD analysis under a dominant model) near the dopamine transporter gene (DAT1). We genotyped 30 single nucleotide polymorphisms (SNPs) in this candidate gene and its 5′ region in 329 families (including the 102 initial families) with 523 affected offspring. We found that (1) SNP rs463379 was significantly associated with ADHD upon correction for multiple testing (P=0.0046); (2) the global P-value for association of haplotypes was significant for block two upon correction for all (n=3) tested blocks (P=0.0048); (3) within block two we detected a nominal P=0.000034 for one specific marker combination. This CGC haplotype showed relative risks of 1.95 and 2.43 for heterozygous and homozygous carriers, respectively; and (4) finally, our linkage data and the genotype-IBD sharing test (GIST) suggest that genetic variation at the DAT1 locus explains our linkage peak and that rs463379 (P<0.05) is the only SNP of the above haplotype that contributed to the linkage signal. In sum, we have accumulated evidence that genetic variation at the DAT1 locus underlies our ADHD linkage peak on chromosome 5; additionally solid association for a single SNP and a haplotype were shown. Future studies are required to assess if variation at this locus also explains other positive linkage results obtained for chromosome 5p.
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References
Faraone SV, Biederman J . Neurobiology of attention-deficit hyperactivity disorder. Biol Psychiatry 1998; 44: 951–958.
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.
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.
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.
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.
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.
Surratt CK, Ukairo OT, Ramanujapuram S . Recognition of psychostimulants, antidepressants, and other inhibitors of synaptic neurotransmitter uptake by the plasma membrane monoamine transporters. AAPS J 2005; 7: E739–E751.
Dresel S, Krause J, Krause KH, LaFougere C, Brinkbauer K, Kung HF et al. Attention deficit hyperactivity disorder: binding of [99mTc]TRODAT-1 to the dopamine transporter before and after methylphenidate treatment. Eur J Nucl Med 2000; 27: 1518–1524.
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 emission computed tomography. Neurosci Lett 2000; 285: 107–110.
Cheon KA, Ryu YH, Kim YK, Namkoong K, Kim CH, Lee JD . Dopamine transporter density in the basal ganglia assessed with [123I]IPT SPET in children with attention deficit hyperactivity disorder. Eur J Nucl Med Mol Imaging 2003; 30: 306–311.
van Dyck CH, Quinlan DM, Cretella LM, Staley JK, Malison RT, Baldwin RM et al. Unaltered dopamine transporter availability in adult attention deficit hyperactivity disorder. Am J Psychiatry 2002; 159: 309–312.
Madras BK, Miller GM, Fischman AJ . The dopamine transporter and attention-deficit/hyperactivity disorder. Biol Psychiatry 2005; 57: 1397–1409.
Giros B, Jaber M, Jones SR, Wightman RM, Caron MG . Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 1996; 379: 606–612.
Gainetdinov RR, Caron MG . Genetics of childhood disorders: XXIV. ADHD, part 8: hyperdopaminergic mice as an animal model of ADHD. J Am Acad Child Adolesc Psychiatry 2001; 40: 380–382.
Spielewoy C, Roubert C, Hamon M, Nosten-Bertrand M, Betancur C, Giros B . Behavioural disturbances associated with hyperdopaminergia in dopamine-transporter knockout mice. Behav Pharmacol 2000; 11: 279–290.
Gainetdinov RR, Wetsel WC, Jones SR, Levin ED, Jaber M, Caron MG . Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 1999; 283: 397–401.
Rodriguiz RM, Chu R, Caron MG, Wetsel WC . Aberrant responses in social interaction of dopamine transporter knockout mice. Behav Brain Res 2004; 148: 185–198.
Rubie C, Schmidt F, Knapp M, Sprandel J, Wiegand C, Meyer J et al. The human dopamine transporter gene: the 5′-flanking region reveals five diallelic polymorphic sites in a Caucasian population sample. Neurosci Lett 2001; 297: 125–128.
Sacchetti P, Mitchell TR, Granneman JG, Bannon MJ . Nurr1 enhances transcription of the human dopamine transporter gene through a novel mechanism. J Neurochem 2001; 76: 1565–1572.
Wang J, Bannon MJ . Sp1 and Sp3 activate transcription of the human dopamine transporter gene. J Neurochem 2005; 93: 474–482.
Greenwood TA, Kelsoe JR . Promoter and intronic variants affect the transcriptional regulation of the human dopamine transporter gene. Genomics 2003; 82: 511–520.
Greenwood TA, Schork NJ, Eskin E, Kelsoe JR . Identification of additional variants within the human dopamine transporter gene provides further evidence for an association with bipolar disorder in two independent samples. Mol Psychiatry 2006; 11: 125–133.
Kelada SN, Costa-Mallen P, Checkoway H, Carlson CS, Weller TS, Swanson PD et al. Dopamine transporter (SLC6A3) 5′ region haplotypes significantly affect transcriptional activity in vitro but are not associated with Parkinson's disease. Pharmacogenet Genomics 2005; 15: 659–668.
Drgon T, Lin Z, Wang GJ, Fowler J, Pablo J, Mash DC et al. Common human 5′ dopamine transporter (SLC6A3) haplotypes yield varying expression levels in vivo. Cell Mol Neurobiol 2006; 26: 875–889.
Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N et al. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Genet 1999; 22: 231–238.
Grunhage F, Schulze TG, Muller DJ, Lanczik M, Franzek E, Albus M et al. Systematic screening for DNA sequence variation in the coding region of the human dopamine transporter gene (DAT1). Mol Psychiatry 2000; 5: 275–282.
Vandenbergh DJ, Thompson MD, Cook EH, Bendahhou E, Nguyen T, Krasowski MD et al. Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations. Mol Psychiatry 2000; 5: 283–292.
Mazei-Robison MS, Couch RS, Shelton RC, Stein MA, Blakely RD . Sequence variation in the human dopamine transporter gene in children with attention deficit hyperactivity disorder. Neuropharmacology 2005; 49: 724–736.
Cook Jr EH, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE et al. Association of attention-deficit disorder and the dopamine transporter gene. Am J Hum Genet 1995; 56: 993–998.
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.
Daly G, Hawi Z, Fitzgerald M, Gill M . Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children. Mol Psychiatry 1999; 4: 192–196.
Bakker SC, van der Meulen EM, Oteman N, Schelleman H, Pearson PL, Buitelaar JK et al. DAT1, DRD4, and DRD5 polymorphisms are not associated with ADHD in Dutch families. Am J Med Genet B Neuropsychiatr Genet 2005; 132: 50–52.
Langley K, Turic D, Peirce TR, Mills S, Van Den Bree MB, Owen MJ et al. No support for association between the dopamine transporter (DAT1) gene and ADHD. Am J Med Genet B Neuropsychiatr Genet 2005; 139: 7–10.
Feng Y, Wigg KG, Makkar R, Ickowicz A, Pathare T, Tannock R et al. Sequence variation in the 3′-untranslated region of the dopamine transporter gene and attention-deficit hyperactivity disorder (ADHD). Am J Med Genet B Neuropsychiatr Genet 2005; 139: 1–6.
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.
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.
Hawi Z, Lowe N, Kirley A, Gruenhage F, Nothen M, Greenwood T et al. Linkage disequilibrium mapping at DAT1, DRD5 and DBH narrows the search for ADHD susceptibility alleles at these loci. Mol Psychiatry 2003; 8: 299–308.
Uhl GR . Dopamine transporter: basic science and human variation of a key molecule for dopaminergic function, locomotion, and parkinsonism. Mov Disord 2003; S7: S71–S80.
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; 11: 934–953.
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn. The American Psychiatric Association (APA): Washington, DC, 1994.
Unnewehr S . Diagnosis of psychiatric disorders in children and adolescents using structured interviews]. Z Kinder Jugendpsychiatr 1995; 23: 121–132.
Barr CL, Xu C, Kroft J, Feng Y, Wigg K, Zai G et al. Haplotype study of three polymorphisms at the dopamine transporter locus confirm linkage to attention-deficit/hyperactivity disorder. Biol Psychiatry 2001; 49: 333–339.
Sauer S, Lechner D, Berlin K, Lehrach H, Escary JL, Fox N et al. A novel procedure for efficient genotyping of single nucleotide polymorphisms. Nucleic Acids Res 2000; 28: E13.
Sauer S, Gut IG . Extension of the GOOD assay for genotyping single nucleotide polymorphisms by matrix-assisted laser desorption/ionization mass spectrometry. Rapid Commun Mass Spectrom 2003; 17: 1265–1272.
Sauer S, Lehrach H, Reinhardt R . MALDI mass spectrometry analysis of single nucleotide polymorphisms by photocleavage and charge-tagging. Nucleic Acids Res 2003; 31: e63.
Sauer S, Kepper P, Smyra A, Dahl A, Ferse FT, Lehrach H et al. Automated solid-phase extraction for purification of single nucleotide polymorphism genotyping products prior to matrix-assisted laser desorption/ionisation time-of-flight mass spectrometric analysis. J Chromatogr A 2004; 1049: 9–16.
Nickerson DA, Tobe VO, Taylor SL . PolyPhred: automating the detection and genotyping of single nucleotide substitutions using fluorescence-based resequencing. Nucleic Acids Res 1997; 25: 2745–2751.
O'Connell JR, Weeks DE . PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am J Hum Genet 1998; 63: 259–266.
Wigginton JE, Abecasis GR . PEDSTATS: descriptive statistics, graphics and quality assessment for gene mapping data. Bioinformatics 2005; 21: 3445–3447.
Becker T, Valentonyte R, Croucher PJ, Strauch K, Schreiber S, Hampe J et al. Identification of probable genotyping errors by consideration of haplotypes. Eur J Hum Genet 2006; 14: 450–458.
Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.
Zhao H, Zhang S, Merikangas KR, Trixler M, Wildenauer DB, Sun F et al. Transmission/disequilibrium tests using multiple tightly linked markers. Am J Hum Genet 2000; 67: 936–946.
Becker T, Knapp M . A powerful strategy to account for multiple testing in the context of haplotype analysis. Am J Hum Genet 2004; 75: 561–570.
Scherag A, Dempfle A, Hinney A, Hebebrand J, Schafer H . Confidence intervals for genotype relative risks and allele frequencies from the case parent trio design for candidate-gene studies. Hum Hered 2002; 54: 210–217.
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.
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.
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.
Li M, Boehnke M, Abecasis GR . Joint modeling of linkage and association: identifying SNPs responsible for a linkage signal. Am J Hum Genet 2005; 76: 934–949.
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.
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.
Janowsky A, Mah C, Johnson RA, Cunningham CL, Phillips TJ, Crabbe JC et al. Mapping genes that regulate density of dopamine transporters and correlated behaviors in recombinant inbred mice. J Pharmacol Exp Ther 2001; 298: 634–643.
Lasky-Su J, Biederman J, Doyle AE, Wilens T, Monuteaux M, Smoller JW et al. Family based association analysis of statistically derived quantitative traits for drug use in ADHD and the dopamine transporter gene. Addict Behav 2006; 31: 1088–1099.
Wang M, Marin A . Characterization and prediction of alternative splice sites. Gene 2006; 366: 219–227.
Matys V, Fricke E, Geffers R, Gossling E, Haubrock M, Hehl R et al. TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res 2003; 31: 374–378.
Zhao Z, Fu YX, Hewett-Emmett D, Boerwinkle E . Investigating single nucleotide polymorphism (SNP) density in the human genome and its implications for molecular evolution. Gene 2003; 312: 207–213.
Acknowledgements
We thank the families for their participation in this study. We thank Professor Joseé Dupuis for stimulating discussions and helpful advices concerning the LAMP method. We thank Gundula Huth for exceptional data management. The German Ministry for Education and Research (National Genome Research Net) and the German Research Foundation (DFG; KFO 125/1-1, SCHA 542/10-2, ME 1923/5-1) financially supported this study.
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Friedel, S., Saar, K., Sauer, S. et al. Association and linkage of allelic variants of the dopamine transporter gene in ADHD. Mol Psychiatry 12, 923–933 (2007). https://doi.org/10.1038/sj.mp.4001986
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DOI: https://doi.org/10.1038/sj.mp.4001986
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