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Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD

Molecular Psychiatry volume 9, pages 169–173 (2004)Cite this article

Abstract

Attention deficit hyperactivity disorder (ADHD) is a childhood onset disorder, for which there is good evidence that genetic factors contribute to the aetiology. Recently reported linkage findings suggested evidence of a susceptibility locus on chromosome 16p13 (maximum LOD score of 4.2, P=5 × 10−6). The GRIN2A (glutamate receptor, ionotropic, N-methyl D-aspartate 2A) gene that encodes the N-methyl D-aspartate receptor subunit 2A (NMDA2A) maps to this region of linkage. As this is also a good functional candidate gene for ADHD, we undertook family-based association analysis in a sample of 238 families. We found significant evidence of association with a GRIN2A exon 5 polymorphism (χ2=5.7, P=0.01). Our data suggest that genetic variation in GRIN2A may confer increased risk for ADHD and that this, at least in part, might be responsible for the linkage result on 16p reported by Smalley et al. We conclude that replication is required and that further work examining for association of GRIN2A polymorphisms with ADHD is warranted.

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References

  1. Nakanishi S, Nakajima Y, Masu M, Ueda Y, Nakahara K, Watanabe D et al. Glutamate receptors: brain function and signal transduction. Brain Res Brain Res Rev 1998; 26: 230–235.

    Article  PubMed  Google Scholar 

  2. Williams NM, Bowen T, Spurlock G, Norton N, Williams NJ, Hoogendoorn B et al. Determination of the genomic structure and mutation screening in schizophrenic individuals for five subunits of the N-methyl-D-aspartate glutamate structure. Mol Psychiatry 2002; 7: 508–514.

    Article  CAS  PubMed  Google Scholar 

  3. Melzer H, Gatward R, Ford T . Mental Health of Children and Adolescents in Great Britain. The Stationery Office: London, 2000.

    Google Scholar 

  4. Barkley RA . Attention-Deficit Hyperactivity Disorder, 2nd edn. The Guilford Press: New York, 1998.

    Book  Google Scholar 

  5. Thapar A . Attention deficit hyperactivity disorder: new genetic findings, new directions. In: Behavioural Genetics in the Postgenomic Era. Plomin R, DeFries J, Craig I, McGuffin P (eds) APA, 2002.

  6. 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  PubMed  PubMed Central  Google Scholar 

  7. Carlsson ML . On the role of cortical glutamate in obsessive-compulsive disorder and attention-deficit hyperactivity disorder, two phenomenologically antithetical conditions. Acta Psych Scand 2000; 102: 401–413.

    Article  CAS  Google Scholar 

  8. Gainetdinov RR, Mohn AR, Bohn LM, Caron MG . Glutamate modulation of hyperactivity in mice lacking the dopamine transporter. Proc Natl Acad Sci USA 2001; 98: 11047–11054.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Mohn AR, Gainetdinov RR, Caron MG, Koller BH . Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell 1999; 98: 427–436.

    Article  CAS  PubMed  Google Scholar 

  10. Ikeda K, Araki K, Takayama C, Inoue Y, Yagi T, Aizawa S et al. Reduced spontaneous activity of mice defective in the epsilon 4 subunit of the NMDA receptor channel. Brain Results Mol Brain Resol 1995; 33: 61–71.

    Article  CAS  Google Scholar 

  11. Sakimura K, Kutsuwada T, Ito I, Manabe T, Takayama C, Kushiya E et al. Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit. Nature 1995; 373: 151–155.

    Article  CAS  PubMed  Google Scholar 

  12. Smalley SL, Kustanovich V, Minassian SL, Stone JL, Ogdie MN, McGough JJ et al. 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  PubMed  PubMed Central  Google Scholar 

  13. Holmes J, Payton A, Barrett JH, Hever T, Fitzpatrick H, Trumper AL et al. A family-based and case–control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder. Mol Psychiatry 2000; 5: 523–530.

    Article  CAS  PubMed  Google Scholar 

  14. Berument SK, Rutter M, Lord C, Pickles A, Bailey A . Autism screening questionnaire: diagnostic validity. Br J Psychiatry 1999; 175: 444–451.

    Article  CAS  PubMed  Google Scholar 

  15. Norton N, Kirov G, Krawczak M, Williams NM, O'Donovan M, Owen M . Universal, robust, highly quantitative SNP allele frequency measurement in DNA pools. Hum Genet 2002; 110: 471–478.

    Article  CAS  PubMed  Google Scholar 

  16. Chen X, Levine L, Kwok PY . Fluorescence polarization in homogenous nucleic acid analysis. Genome Res 1999; 9: 492–498.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Clayton D . A generalization of the transmission/disequilibrium test for uncertain haplotype transmission. Am J Hum Genet 1999; 65: 1170–1177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Castellanos FX . Neuroimaging studies of ADHD. In: Stimulant Drugs and ADHD. Basic and Clinical Neuroscience. Solanto M, Arnsten A, Castellanos F (eds). Oxford University Press: Oxford, 2001, pp 243–258.

    Google Scholar 

  19. Rubia K, Taylor E, Smith AB, Oksannen H, Overmeyer S, Newman S . Neuropsychological analyses of impulsiveness in childhood hyperactivity. Br J Psychiatry 2001; 179: 138–143.

    Article  CAS  PubMed  Google Scholar 

  20. Castellanos FX, Lee PP, Sharp W, Jeffries NO, Greenstein DK, Clasen LS et al. Developmental trajectories of brain volume abnormalities in children and adolescents with attention-deficit/hyperactivity disorder. JAMA 2002; 288: 1740–1748.

    Article  PubMed  Google Scholar 

  21. Carlsson M, Carlsson A . Interactions between glutamatergic and monoaminergic systems within the basal ganglia — implications for Schizophrenia and Parkinsons-disease. Trends Neurosci 1990; 13: 272–276.

    Article  CAS  PubMed  Google Scholar 

  22. Grace AA . Psychostimulant actions on dopamine and limbic system function: relevance to the pathophysical and treatment of ADHD. In: Stimulant Drugs and ADHD. Basic and Clinical Neuroscience. Solanto M, Arnsten A, Castellanos F (eds). Oxford University Press: Oxford, 2001, pp 134–157.

    Google Scholar 

  23. Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M et al. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 2000; 26: 163–175.

    Article  CAS  PubMed  Google Scholar 

  24. Rioux JD, Daly MJ, Silverberg MS, Lindblad K, Steinhart H, Cohen Z et al. Genetic variation in the 5q31 cytokine gene cluster confers susceptibility to Crohn disease. Nat Genet 2001; 29: 223–228.

    Article  CAS  PubMed  Google Scholar 

  25. Bray NJ, Buckland P, Owen MJ, O'Donovan MC . Cis-acting mechanisms affect the expression of a high proportion of genes in human brain, submitted.

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Acknowledgements

This work is supported by the Wellcome Trust. Jane Holmes, Tracey Hever and Helen Pay were involved in the first wave of data collection. We thank all the clinicians and especially all the families who participated in this study.

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Authors and Affiliations

  1. Department of Psychological Medicine, University of Wales College of Medicine, Cardiff, UK

    D Turic, K Langley, S Mills, M Stephens, D Lawson, C Govan, N Williams, M Van den Bree, M Owen, M O'Donovan & A Thapar

  2. Department of Psychiatry, University of Birmingham, Birmingham, UK

    N Craddock & L Kent

Authors
  1. D Turic
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  2. K Langley
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  3. S Mills
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  4. M Stephens
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  7. N Williams
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  8. M Van den Bree
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  11. M Owen
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  12. M O'Donovan
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  13. A Thapar
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Corresponding authors

Correspondence to M O'Donovan or A Thapar.

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Turic, D., Langley, K., Mills, S. et al. Follow-up of genetic linkage findings on chromosome 16p13: evidence of association of N-methyl-D aspartate glutamate receptor 2A gene polymorphism with ADHD. Mol Psychiatry 9, 169–173 (2004). https://doi.org/10.1038/sj.mp.4001387

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  • DOI: https://doi.org/10.1038/sj.mp.4001387

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