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Synaptosomal-associated protein 25 (SNAP-25) and attention deficit hyperactivity disorder (ADHD): evidence of linkage and association in the Irish population

Molecular Psychiatry volume 7, pages 913–917 (2002)Cite this article

Abstract

Several lines of evidence have suggested that ADHD is a polygenic disorder produced by the interaction of several genes each of a minor effect. Synaptosomal-associated protein 25 (SNAP-25) is a presynaptic plasma membrane protein which is expressed highly and specifically in the nerve cells. The gene encodes a protein essential for synaptic vesicle fusion and neurotransmitter release. Animal model studies showed that the coloboma mouse mutant has a hyperactive phenotype similar to that of ADHD. The hyperactive phenotype of this model has been shown to be the result of a deletion of the SNAP-25 gene. DNA variations within or closely mapped to the SNAP-25 gene may alter the level of expression and hence may have an effect on the function of synaptic vesicle fusion and neurotransmitter release. Using HHRR and TDT we analysed 93 ADHD nuclear families from Ireland and found increased preferential transmission of SNAP-25/DdeI allelel to ADHD cases; HHRR (χ2 = 6.55, P = 0.01) and linkage (TDT) (χ2 = 6.5, P = 0.015). In contrast to our findings, Barr et al1 reported an increased transmission of allele 2 of the DdeI polymorphism though this was not statistically significant. However, they also reported a significantly increased transmission of a haplotype (made of allele 1 of MnlI and allele 2 of the DdeI) in their Canadian ADHD sample. It is not clear what the role of SNAP-25 in ADHD is until these findings are either confirmed or refuted in other ADHD samples.

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References

  1. Barr CL, Feng Y, Wigg K, Bloom S, Roberts W, Malone M et al. Identification of DNA variants in the SNAP-25 gene and linkage study of these polymorphisms and attention-deficit hyperactivity disorder Mol Psychiatry 2000; 5: 405–409

    Article  CAS  PubMed  Google Scholar 

  2. Barkley RA . Attention-deficit hyperactivity disorder Scientific American 1998; 279: 66–71

    Article  CAS  PubMed  Google Scholar 

  3. Tannock R . Attention deficit hyperactivity disorder: advances in cognitive, neurobiological and genetic research J Child Psychol Psychiatry 1998; 39: 65–99

    Article  CAS  PubMed  Google Scholar 

  4. Zametkin AJ, Nordahl TE, Gross J, King AC, Semple WE, Rumsey J et al. Cerebral glucose metabolism in adults with hyperactivity of childhood onset New Eng J Med 1990; 323: 1361–1366

    Article  CAS  PubMed  Google Scholar 

  5. 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 in psychiatrically and pediatrically referred samples Arch Gen Psychiatry 1992; 49: 728–738

    Article  CAS  PubMed  Google Scholar 

  6. Gillis JJ, Gilger JW, Pennington BF, DeFries JC . Attention deficit disorder in reading-disabled twins: evidence for a genetic aetiology J Abnorm Child Psychol 1992; 20: 303–315

    Article  CAS  PubMed  Google Scholar 

  7. Sherman DK, Iacona WG, McGue M . Attention-deficit hyperactivity disorder dimensions: a twin study of attention and impulsivity-hyperactivity J Am Acad Child Adolesc Psychiatry 1997; 36: 745–753

    Article  CAS  PubMed  Google Scholar 

  8. Levy F, Hay DA, McStephen M, Wood C, Waldman I . Attention-deficit hyperactivity disorder: a category or a continuum? Genetic analysis of a large-scale twin study J Am Acad Child Adolesc Psychiatry 1997; 36: 737–744

    Article  CAS  PubMed  Google Scholar 

  9. Sprich S, Biederman J, Crawford MH, Mundy E, Faraone SV . Adoptive and biological families of children and adolescents with ADHD J Am Acad Child Adolesc Psychiatry 2000; 39: 1432–1437

    Article  CAS  PubMed  Google Scholar 

  10. Greenhill LL . Pharmacologic treatment of attention deficient hyperactivity disorder Psychiatr Clin North Am 1992; 15: 1–27

    Article  CAS  PubMed  Google Scholar 

  11. Giros B, Jaber M, Jones S, Wightman RM, Caron MG . Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter Nature 1996; 379: 606–612

    Article  CAS  PubMed  Google Scholar 

  12. Cook EH, Stein MA, Krasowski MD, Cox NJ, Olkon DM, Kieffer JE, Leventhal BL . Association of attention deficit disorder and the dopamine transporter gene Am J Hum Genet 1995; 56: 993–998

    CAS  PubMed  PubMed Central  Google Scholar 

  13. LaHoste GJ, Swanson JM, Wigal SB, Glabe C, Wigal T, King N, Kennedy JL . Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder Mol Psychiatry 1996; 1: 121–124

    CAS  PubMed  Google Scholar 

  14. 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

    Article  CAS  PubMed  Google Scholar 

  15. Castellanos FX, Lewczyk CM, Fernandez T, Koprivica V, Kashani A, Tayebi N et al. Lack of an association between dopamine transporter (DAT1) and ADHD Mol Psychiatry 1999; 4: S80

    Article  Google Scholar 

  16. Hawi Z, McCarron M, Kirley K, Fitzgerald M, Gill M . No association of the dopamine DRD4 receptor (DRD4) gene polymorphism with attention deficit hyperactivity disorder (ADHD) in the Irish population Am J Med Genet (Neuropsych Genet) 2000; 96: 268–272

    Article  CAS  Google Scholar 

  17. Sollner T, Whiteheart SW, Brunner M, Erdjument-Bromage H, Geromanos S, Tempst P, Rothman JE . SNAP receptors implicated in vesicle targeting and fusion Nature 1993; 362: 318–324

    Article  CAS  PubMed  Google Scholar 

  18. Hess EJ, Collins KA, Wilson MC . Mouse model for hyperkinesis implicates SNAP in behavioural regulation J Neurosci 1996; 16: 3104–3111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Maglott DR, Feldblyum TV, Durkin AS, Nierman WC . Radiation hybrids mapping of SNAP, PCSK2 and THBD (human chromosome 20p) Mamm Genome 1996; 7: 400–401

    Article  CAS  PubMed  Google Scholar 

  20. Wilson MC . Coloboma mouse mutant as an animal model of hyperkenesis and attention deficit hyperactivity disorder Neurosci Biobehav Rev 2000; 24: 51–57

    Article  CAS  PubMed  Google Scholar 

  21. Raber J, Mehta PP, Kreifeldt M, Parsons LH, Weiss F, Bloom FE, Wilson MC . Coloboma hyperactive mutant mice exhibit regional and transmitter-specific deficits in neurotransmission J Neurochem 1997; 68: 176–186

    Article  CAS  PubMed  Google Scholar 

  22. Barkley RA . Attention-deficit/hyperactivity disorder, self-regulation, and time: toward a more comprehensive theory Dev Behav Pediatrics 1997; 18: 271–279

    CAS  Google Scholar 

  23. Kirley A, Hawi Z, Daly G, McCarron M, Mullins C, Millar N, Fitzgerald M, Gill M . Dopaminergic system genes in ADHD: towards a biological hypothesis Neuropsychopharmacology (in press)

  24. Hayward BE, Kamiya M, Strain L, Moran V, Campbell R, Hayashizaki Y, Bonthron DT . The human GNAS1 gene is imprinted and encodes distinct paternally and biallelically expressed G proteins Proc Natl Acad Sci USA 1998; 95: 10038–10043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hess EJ, Rogan PK, Domoto M, Tinker DE, Ladda RL, Ramer JC . Absence of linkage of apparently single gene mediated ADHD with the human syntenic region of the mouse mutant Coloboma Am J Med Genet 1995; 60: 573–579

    Article  CAS  PubMed  Google Scholar 

  26. Ward MF, Wender PH, Reimherr FW . The Wender Utah Rating Scale: an aid in the retrospective diagnosis of childhood attention deficit hyperactivity disorder Am J Psychiatry 1993; 150: 885–890

    Article  CAS  PubMed  Google Scholar 

  27. Terwilliger JD, Ott J . ‘A haplotype based haplotype relative risk’ approach to detecting allelic association Hum Hered 1992; 42: 337–346

    Article  CAS  PubMed  Google Scholar 

  28. Spielman RS, McGinnis RE, Ewens WJ . Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM) Am J Hum Genet 1993; 52: 506–516

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Terwilliger J, Ott J . Handbook for Human Genetic Linkage Johns Hopkins University Press: Baltimore 1994

    Google Scholar 

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Acknowledgements

We would like to acknowledge the generous support of the Health Research Board, Dublin, The Wellcome Trust (ZH and AK), and the Hyperactive and Attention Disorder (HAD) Group Ireland. We would also like to thank the families who participated in the study.

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Authors and Affiliations

  1. Department of Genetics and Psychiatry, Trinity College, Dublin, 2, Ireland

    K Brophy, Z Hawi, A Kirley, M Fitzgerald & M Gill

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  1. K Brophy
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  2. Z Hawi
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  3. A Kirley
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  4. M Fitzgerald
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  5. M Gill
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Correspondence to Z Hawi.

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Brophy, K., Hawi, Z., Kirley, A. et al. Synaptosomal-associated protein 25 (SNAP-25) and attention deficit hyperactivity disorder (ADHD): evidence of linkage and association in the Irish population. Mol Psychiatry 7, 913–917 (2002). https://doi.org/10.1038/sj.mp.4001092

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