1. ¹Department of Psychiatry and Psychotherapy (Section for Clinical and Molecular Psychobiology and Laboratory for Psychophysiology and Functional Imaging), Julius-Maximilians-University Würzburg, Würzburg, Germany
2. ²Central Laboratory, Department of Clinical Biochemistry and Pathobiochemistry, University of Würzburg, Würzburg, Germany
3. ³Department of Differential and Personality Psychology, Institute of Psychology II, Technische Universität Dresden, Dresden, Germany
4. ⁴Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany
5. ⁵Department of Internal Medicine II, Technical University of München, München, Germany

Correspondence: Dr A Reif, Section for Molecular and Clinical Psychobiology, Department of Psychiatry and Psychotherapy, University of Würzburg, Füchsleinstr. 15, D-97080 Würzburg, Germany. E-mail: a.reif@gmx.net

Received 28 July 2005; Revised 1 November 2005; Accepted 7 November 2005; Published online 3 January 2006.

Abstract

Nitric oxide (NO) is a gaseous neurotransmitter thought to play important roles in several behavioral domains. On a neurobiological level, NO acts as the second messenger of the N-methyl-D-aspartate receptor and interacts with both the dopaminergic as well as the serotonergic system. Thus, NO is a promising candidate molecule in the pathogenesis of endogenous psychoses and a potential target in their treatment. Furthermore, the chromosomal locus of the gene for the NO-producing enzyme NOS-I, 12q24.2, represents a major linkage hot spot for schizophrenic and bipolar disorder. To investigate whether the gene encoding NOS-I (NOS1) conveys to the genetic risk for those diseases, five NOS1 polymorphisms as well as a NOS1 mini-haplotype, consisting of two functional polymorphisms located in the transcriptional control region of NOS1, were examined in 195 chronic schizophrenic, 72 bipolar-I patients and 286 controls. Single-marker association analysis showed that the exon 1c promoter polymorphism was linked to schizophrenia (SCZ), whereas synonymous coding region polymorphisms were not associated with disease. Long promoter alleles of the repeat polymorphism were associated with less severe psychopathology. Analysis of the mini-haplotype also revealed a significant association with SCZ. Mutational screening did not detect novel exonic polymorphisms in patients, suggesting that regulatory rather than coding variants convey the genetic risk on psychosis. Finally, promoter polymorphisms impacted on prefrontal functioning as assessed by neuropsychological testing and electrophysiological parameters elicited by a Go-Nogo paradigm in 48 patients (continuous performance test). Collectively these findings suggest that regulatory polymorphisms of NOS1 contribute to the genetic risk for SCZ, and modulate prefrontal brain functioning.