J Oliveira1,2, M Debnath1,2, B Etain2,3,4,5, M Bennabi1,2, N Hamdani2,3,4,5, M Lajnef2,3,4, D Bengoufa6, C Fortier6, W Boukouaci1, F Bellivier2,3,4,5, J-P Kahn2,7, C Henry2,3,4,5, D Charron1,2,6,8, R Krishnamoorthy1, M Leboyer2,3,4,5, R Tamouza1,2,6,8. 1. INSERM, U1160, Hôpital Saint Louis, Paris, France. 2. Fondation FondaMental, Créteil, France. 3. INSERM, U955, Psychopathologie et Génétique des maladies psychiatriques, Créteil, France. 4. Faculté de Médecine, Université Paris-Est, Créteil, France. 5. AP-HP, Pôle de Psychiatrie et d'Addictologie des Hôpitaux Universitaires Henri Mondor, Créteil, France. 6. Laboratoire Jean Dausset and LabEx Transplantex, Hôpital Saint Louis, Paris, France. 7. Service de Psychiatrie et Psychologie Clinique, CHU de Nancy, Hôpitaux de Brabois, Vandoeuvre Les Nancy, France. 8. Sorbonne Paris-Cité, Université Paris Diderot, Paris, France.
Abstract
OBJECTIVE: Given the importance of nitric oxide system in oxidative stress, inflammation, neurotransmission and cerebrovascular tone regulation, we postulated its potential dysfunction in bipolar disorder (BD) and suicide. By simultaneously analysing variants of three isoforms of nitric oxide synthase (NOS) genes, we explored interindividual genetic liability to suicidal behaviour in BD. METHOD: A total of 536 patients with BD (DSM-IV) and 160 healthy controls were genotyped for functionally relevant NOS1, NOS2 and NOS3 polymorphisms. History of suicidal behaviour and violent suicide attempt was documented for 511 patients with BD. Chi-squared test was used to perform genetic association analyses and logistic regression to test for gene-gene interactions. RESULTS: NOS3 rs1799983 T homozygous state was associated with violent suicide attempts (26.4% vs. 10.8%, in patients and controls, P = 0.002, corrected P (Pc) = 0.004, OR: 2.96, 95% CI = 1.33-6.34), and this association was restricted to the early-onset BD subgroup (37.9% vs. 10.8%, in early-onset BD and controls, P = 0.0003, Pc = 0.0006 OR: 5.05, 95% CI: 1.95-12.45), while we found no association with BD per se and no gene-gene interactions. CONCLUSION: Our results bring further evidence for the potential involvement of endothelial NOS gene variants in susceptibility to suicidal behaviour. Future exploration of this pathway on larger cohort of suicidal behaviour is warranted.
OBJECTIVE: Given the importance of nitric oxide system in oxidative stress, inflammation, neurotransmission and cerebrovascular tone regulation, we postulated its potential dysfunction in bipolar disorder (BD) and suicide. By simultaneously analysing variants of three isoforms of nitric oxide synthase (NOS) genes, we explored interindividual genetic liability to suicidal behaviour in BD. METHOD: A total of 536 patients with BD (DSM-IV) and 160 healthy controls were genotyped for functionally relevant NOS1, NOS2 and NOS3 polymorphisms. History of suicidal behaviour and violent suicide attempt was documented for 511 patients with BD. Chi-squared test was used to perform genetic association analyses and logistic regression to test for gene-gene interactions. RESULTS:NOS3rs1799983 T homozygous state was associated with violent suicide attempts (26.4% vs. 10.8%, in patients and controls, P = 0.002, corrected P (Pc) = 0.004, OR: 2.96, 95% CI = 1.33-6.34), and this association was restricted to the early-onset BD subgroup (37.9% vs. 10.8%, in early-onset BD and controls, P = 0.0003, Pc = 0.0006 OR: 5.05, 95% CI: 1.95-12.45), while we found no association with BD per se and no gene-gene interactions. CONCLUSION: Our results bring further evidence for the potential involvement of endothelial NOS gene variants in susceptibility to suicidal behaviour. Future exploration of this pathway on larger cohort of suicidal behaviour is warranted.
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