A NOS-III haplotype that includes functional polymorphisms is associated with bipolar disorder

Int J Neuropsychopharmacol. 2006 Feb;9(1):13-20. doi: 10.1017/S1461145705005560. Epub 2005 Jun 21.


The pleiotropic messenger molecule nitric oxide (NO) has been implicated in a variety of higher CNS functions, including learning, memory, and emotionality. In the human brain, NO is predominantly formed by neuronal NO synthase (NOS-I), while the so-called 'endothelial' isoform NOS-III also contributes to NO generation. We recently reported that NOS-III knockout mice display decreased adult neurogenesis and reduced responsiveness in a learned helplessness paradigm. To examine whether NOS-III plays a role in affective disorders as well, we tested a NOS-III gene haplotype, consisting of three functional polymorphisms, for an association with bipolar disorder and major depression. A significant global haplotype association with bipolar disorder (n = 284 controls; n = 91 patients; p(global) = 0.021; p(t-a-g) < 0.001), but not unipolar depression (n = 45) was detected. Our results thus suggest that the NOS-III genotype may convey a modest genetic risk to develop bipolar disorder. This finding should be further clarified by the use of within-family designs and in samples of other ethnicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bipolar Disorder / etiology
  • Bipolar Disorder / genetics*
  • Depressive Disorder, Major / genetics
  • Female
  • Genetic Predisposition to Disease
  • Haplotypes
  • Humans
  • Male
  • Nitric Oxide Synthase Type III / genetics*
  • Polymorphism, Single Nucleotide
  • Risk Factors


  • NOS3 protein, human
  • Nitric Oxide Synthase Type III