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  • Original Research Article
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Allelic association of the neuronal nitric oxide synthase (NOS1) gene with schizophrenia

Abstract

Nitric oxide (NO) has been identified as a widespread and multifunctional biological messenger molecule in the central nervous system (CNS), with possible roles in neurotransmission, neurosecretion, synaptic plasticity, and tissue injury in many neurological disorders, including schizophrenia. Neuronal NO is widely produced in the brain from L-arginine catalyzed by neuronal NO synthase (NOS1). We therefore hypothesized that the NOS1 gene may play a role in the pathophysiology of schizophrenia. In the present study, we examined the genetic association between a novel single nucleotide polymorphism (SNP: a C→T transition located 276 base pairs downstream from the translation termination site) of the human NOS1 gene, which is located in chromosome 12q24, and schizophrenia (215 Japanese patients with schizophrenia and 182 healthy controls). The allele frequencies of the polymorphism in exon 29 of the NOS1 gene differed significantly between patients with schizophrenia and controls (χ2 = 20.10, df = 1, P = 0.000007; relative risk = 1.92; 95% confidence interval = 1.44–2.55). Our results suggest that the NOS1 gene polymorphism may confer increased susceptibility to schizophrenia.

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References

  1. Krukoff TL . Central actions of nitric oxide in regulation of autonomic functions Brain Res Brain Res Rev 1999 30: 52–65

    Article  CAS  Google Scholar 

  2. Yun HY, Dawson VL, Dawson TM . Nitric oxide in health and disease of the nervous system Mol Psychiatry 1997 2: 300–310

    Article  CAS  Google Scholar 

  3. Arnold WP, Mittal CK, Katsuki S, Murad F . Nitric oxide activates guanylate cyclase and increases guanosine 3′: 5′-cyclic monophosphate levels in various tissue preparations Proc Natl Acad Sci USA 1977 74: 3203–3207

    Article  CAS  Google Scholar 

  4. Bredt DS, Snyder SH . Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum Proc Natl Acad Sci USA 1989 86: 9030–9033

    Article  CAS  Google Scholar 

  5. Garthwaite J . Glutamate, nitric oxide and cell-cell signalling in the nervous system Trends Neurosci 1991 14: 60–67

    Article  CAS  Google Scholar 

  6. Medina JH, Izquierdo I . Retrograde messengers, long-term potentiation and memory Brain Res Brain Res Rev 1995 21: 185–194

    Article  CAS  Google Scholar 

  7. O'Dell TJ, Hawkins RD, Kandel ER, Arancio O . Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger Proc Natl Acad Sci USA 1991 88: 11285–11289

    Article  CAS  Google Scholar 

  8. Vincent SR . Nitric oxide: a radical neurotransmitter in the central nervous system Prog Neurobiol 1994 42: 129–160

    Article  CAS  Google Scholar 

  9. Yun HY, Dawson VL, Dawson TM . Neurobiology of nitric oxide Crit Rev Neurobiol 1996 10: 291–316

    Article  CAS  Google Scholar 

  10. Reddy R, Sahebarao MP, Mukherjee S, Murthy JN . Enzymes of the antioxidant defense system in chronic schizophrenic patients Biol Psychiatry 1991 30: 409–412

    Article  CAS  Google Scholar 

  11. Mukerjee S, Mahadik SP, Scheffer R, Correnti EE, Kelkar H . Impaired antioxidant defense at the onset of psychosis Schizophr Res 1996 19: 19–26

    Article  CAS  Google Scholar 

  12. Mahadik SP, Mukherjee S, Correnti EE, Scheffer R . Elevated levels of lipid peroxidation products in plasma of drug-naive patients at the onset of psychosis Schizophr Res 1995 15: 66

    Google Scholar 

  13. Horrobin DF, Manku MS, Hillman H, Iain A, Glen M . Fatty acid levels in the brains of schizophrenics and normal controls Biol Psychiatry 1991 30: 795–805

    Article  CAS  Google Scholar 

  14. Bredt DS, Hwang PM, Glatt CE, Lowenstein C, Reed RR, Snyder SH . Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase Nature 1991 351: 714–718

    Article  CAS  Google Scholar 

  15. Xie QW, Cho HJ, Calaycay J, Mumford RA, Swiderek KM, Lee TD et al. Cloning and characterization of inducible nitric oxide synthase from mouse macrophages Science 1992 256: 225–228

    Article  CAS  Google Scholar 

  16. Lowenstein CJ, Glatt CS, Bredt DS, Snyder SH . Cloned and expressed macrophage nitric oxide synthase contrasts with the brain enzyme Proc Natl Acad Sci USA 1992 89: 6711–6715

    Article  CAS  Google Scholar 

  17. Lyons CR, Orloff GJ, Cunningham JM . Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line J Biol Chem 1992 267: 6370–6374

    CAS  PubMed  Google Scholar 

  18. Vincent SR, Hope BT . Neurons that say NO Trends Neurosci 1992 15: 108–113

    Article  CAS  Google Scholar 

  19. Snyder SH . Nitric oxide: first in a new class of neurotransmitters Science 1992 257: 494–496

    Article  CAS  Google Scholar 

  20. Garthwaite J, Garthwaite G, Palmer RM, Moncada S . NMDA receptor activation induces nitric oxide synthesis from arginine in rat brain slices Eur J Pharmacol 1989 172: 413–416

    Article  CAS  Google Scholar 

  21. Kishimoto J, Spurr N, Liao M, Lizhi L, Emson P, Xu W . Localization of brain nitric oxide synthase (NOS) to human chromosome 12 Genomics 1992 14: 802–804

    Article  CAS  Google Scholar 

  22. Grasemann H, Yandava CN, Drazen JM . Neuronal NO synthase (NOS1) is a major candidate gene for asthma Clin Exp Allergy 1999 29 (Suppl 4): 39–41

    Google Scholar 

  23. Hall AV, Antoniou H, Wang Y, Cheung AH, Arbus AM, Olson SL et al. Structural organization of the human neuronal nitric oxide synthase gene (NOS1) J Biol Chem 1994 269: 33082–33090

    CAS  Google Scholar 

  24. Wang Y, Newton DC, Marsden PA . Neuronal NOS: gene structure, mRNA diversity, and functional relevance Crit Rev Neurobiol 1999 13: 21–43

    Article  Google Scholar 

  25. Martin ER, Lai EH, Gilbert JR, Rogala AR, Afshari AJ, Riley J et al. SNPing away at complex diseases: analysis of single-nucleotide polymorphisms around APOE in Alzheimer disease Am J Hum Genet 2000 67: 383–394

    Article  CAS  Google Scholar 

  26. Cadet JL, Kahler LA . Free radical mechanisms in schizophrenia and tardive dyskinesia Neurosci Biobehav Rev 1994 18: 457–467

    Article  CAS  Google Scholar 

  27. Reddy RD, Yao JK . Free radical pathology in schizophrenia: a review Prostaglandins Leukot Essent Fatty Acids 1996 55: 33–43

    Article  CAS  Google Scholar 

  28. Mahadik SP, Mukherjee S . Free radical pathology and antioxidant defense in schizophrenia: a review Schizophr Res 1996 19: 1–17

    Article  CAS  Google Scholar 

  29. Yao JK, Reddy R, van Kammen DP . Reduced level of plasma antioxidant uric acid in schizophrenia Psychiatry Res 1998 80: 29–39

    Article  CAS  Google Scholar 

  30. Mahadik SP, Scheffer RE . Oxidative injury and potential use of antioxidants in schizophrenia Prostaglandins Leukot Essent Fatty Acids 1996 55: 45–54

    Article  CAS  Google Scholar 

  31. Yao JK, Reddy R, McElhinny LG, van Kammen DP . Effects of haloperidol on antioxidant defense system enzymes in schizophrenia J Psychiatr Res 1998 32: 385–391

    Article  CAS  Google Scholar 

  32. Lin A, Kenis G, Bignotti S, Tura GJ, De Jong R, Bosmans E et al. The inflammatory response system in treatment-resistant schizophrenia: increased serum interleukin-6 Schizophr Res 1998 32: 9–15

    Article  CAS  Google Scholar 

  33. Bird DC, Bujas-Bobanovic M, Robertson HA, Dursun SM . Lack of phencyclidine-induced effects in mice with reduced neuronal nitric oxide synthase Psychopharmacology 2001 155: 299–309

    Article  CAS  Google Scholar 

  34. Smythies J . Redox aspects of signaling by catecholamines and their metabolites Antioxid Redox Signal 2000 2: 575–583

    Article  CAS  Google Scholar 

  35. Smythies JR . Oxidative reactions and schizophrenia: a review-discussion Schizophr Res 1997 24: 357–364

    Article  CAS  Google Scholar 

  36. Hori H, Ohmori O, Shinkai T, Kojima H, Okano C, Suzuki T et al. Manganese superoxide dismutase gene polymorphism and schizophrenia: relation to tardive dyskinesia Neuropsychopharmacology 2000 23: 170–177

    Article  CAS  Google Scholar 

  37. Hope BT, Michael GJ, Knigge KM, Vincent SR . Neuronal NADPH diaphorase is a nitric oxide synthase Proc Natl Acad Sci USA 1991 88: 2811–2814

    Article  CAS  Google Scholar 

  38. Karson CN, Garcia-Rill E, Biedermann J, Mrak RE, Husain MM, Skinner RD . The brain stem reticular formation in schizophrenia Psychiatry Res 1991 40: 31–48

    Article  CAS  Google Scholar 

  39. Garcia-Rill E, Biedermann JA, Chambers T, Skinner RD, Mrak RE, Husain M et al. Mesopontine neurons in schizophrenia Neuroscience 1995 66: 321–335

    Article  CAS  Google Scholar 

  40. Akbarian S, Vinuela A, Kim JJ, Potkin SG, Bunney WE Jr, Jones EG . Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development Arch Gen Psychiatry 1993 50: 178–187

    Article  CAS  Google Scholar 

  41. Akbarian S, Bunney WE Jr, Potkin SG, Wigal SB, Hagman JO, Sandman CA et al. Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development Arch Gen Psychiatry 1993 50: 169–177

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors wish to thank Dr Yoshitaro Mine from Wakato Hospital, Dr Akira Eto from Komine-Eto Hospital, Dr Yasuhiro Tsutsumi from Tsutsumi-Kokura Hospital, Dr Kenji Yamaura from Matsugae Hospital, and Dr Takaharu Hayashida from Mitate Hospital for their referral of patients.

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Correspondence to O Ohmori.

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Shinkai, T., Ohmori, O., Hori, H. et al. Allelic association of the neuronal nitric oxide synthase (NOS1) gene with schizophrenia. Mol Psychiatry 7, 560–563 (2002). https://doi.org/10.1038/sj.mp.4001041

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