A putative cis-acting polymorphism in the NOS1 gene is associated with schizophrenia and NOS1 immunoreactivity in the postmortem brain

Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. Recent genome-wide scans revealed that rare structural variants disrupted multiple genes in neurodevelopmental pathways, which strongly implicate nitric oxide (NO) signaling in schizophrenia. NO acts as a second messenger of N-methyl-D aspartate receptor activation, which further interacts with both dopaminergic and serotonergic pathways. NO is mainly synthesized by neuronal nitric oxide synthase (NOS1) in the brain, and its gene locus, 12q24.2, has attracted much attention as a major linkage region for schizophrenia. Genetic variations of NOS1 have also been associated with schizophrenia, and differential expression of NOS1 was observed in the postmortem brain of schizophrenic patients. Here, we explored the hypothesis that a putative cis-acting G-84A single nucleotide polymorphism (SNP; rs41279104) in the exon 1c promoter region of the NOS1 gene is associated with the levels of NOS1 immunoreactivity in postmortem prefrontal cortex specimens regardless of disease phenotype. Individuals with the A-allele of this SNP showed significantly lower levels of NOS1 immunoreactivity than did GG homozygotes (p=0.002). Furthermore, a case-control study using 720 individuals in a Japanese population revealed a significant association between the SNP and schizophrenia (genotypic p=0.0013 and allelic p=0.0011). Additionally, the average of onset age in schizophrenic patients with the A-allele was significantly earlier than GG homozygotes (p=0.018). When the analyses took gender into account, this significance was more significant for female. These findings provide further evidences that NOS1 is associated with a biological susceptibility gene to schizophrenia.