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

The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis

“…Ethnic differences in the investigated samples have also been taken into account, as different LD structures in different populations might obscure the linkage with "true" underlying risk variants. On the pathophysiological level, our data is at odds with three other studies arguing for unchanged (Cui et al, 2010) or even increased (Baba et al, 2004;Silberberg et al, 2010) NOS1 expression in schizophrenia. As the study by Cui and associates also found reduced NOS1 expression in risk allele carriers, one might rather assume that reduced NOS1 expression is not to be found in schizophrenia as a whole but rather there is a genetically distinct schizophrenia sub-group that is characterized by compromised NO signaling, while other sub-groups might display compensatory upregulation of NOS1.…”

“…Odds ratios were in the expected range for common variants, although the NOS1 promoter polymorphism rs41279104 conveyed a relatively high risk with an OR=1.3. Most interestingly, following initial studies arguing for an effect of this SNP on reporter gene expression in heterologous cell systems, we could extend this data here by showing that the risk allele resulted in lower NOS1 expression in the prefrontal cortex which is in line with data showing reduced NOS-I immunohistochemical staining in the prefrontal cortex in risk allele carriers (Cui et al, 2010). To clarify molecular function of rs41279104 and six high LD proxy SNPs on NOS1 expression in greater detail, we used several in silico approaches which revealed that the SNPs' minor alleles replace putative binding sites for transcription factors that are known to be expressed in the prefrontal cortex; this provides a possible mechanism how rs41279104 by means of its proxies may influence NOS1 expression.…”

“…Titles and abstracts were scrutinized to exclude non-genetic studies, reducing the number of included studies to Costain et al, 2010;Fang et al, 2008;Greenwood et al, 2011;Husted et al, 2010;Kremeyer et al, 2009;Miranda et al, 2006;Nicodemus et al, 2008;Wratten et al, 2009) and one on NOS1 (Fallin et al, 2005), presented family-based, but not case-control data and were therefore not integrated in the meta-analysis for methodological reasons. The remaining studies on NOS1AP (n=6; (Aberg et al, 2010;Delorme et al, 2010;Nicodemus et al, 2010;Puri et al, 2007;Puri et al, 2006;Zheng et al, 2005)) and NOS1 (n=14; (Cui et al, 2010;Donohoe et al, 2009;Kawohl et al, 2008;Nicodemus et al, 2010;O'Donoghue et al, 2012;Okumura et al, 2009;Reif et al, 2006;Reif et al, 2011;Riley et al, 2010;Rose et al, 2012;Shinkai et al, 2002;Silberberg et al, 2010;Tang et al, 2008;Wang et al, 2012)) reported on case-control association data and were scrutinized in greater detailed. For NOS1AP, two and for NOS1, 11 further studies had to be excluded from meta-analysis for the following reasons.…”

“…Subsequently, our group conducted a mutation analysis, qRT PCR and haplotype analysis in Caucasian patients suffering from schizophrenia arguing that a functional promoter SNP (rs41279104), resulting in decreased expression of a reporter gene in cell culture experiments (Saur et al, 2004), is associated with disease (Reif et al, 2006a). Since then, six more case-control association studies on schizophrenia and NOS1 were published in total (Cui et al, 2010;Nicodemus et al, 2010;Okumura et al, 2009;Riley et al, 2010;Tang et al, 2008;Wang et al, 2012). Four of those came from Asian populations (two Chinese and two Japanese (Cui et al, 2010;Okumura et al, 2009)), with mixed results: while Cui and associates replicated the positive finding on rs41279104 (and also provided evidence for reduced NOS-I expression on the protein level in BA9 -part of the dorsolateral prefrontal cortex -for risk allele carriers), Okumura could not, although two other NOS1 SNPs were significant (but did not survive correction for multiple testing).…”

“…Since then, six more case-control association studies on schizophrenia and NOS1 were published in total (Cui et al, 2010;Nicodemus et al, 2010;Okumura et al, 2009;Riley et al, 2010;Tang et al, 2008;Wang et al, 2012). Four of those came from Asian populations (two Chinese and two Japanese (Cui et al, 2010;Okumura et al, 2009)), with mixed results: while Cui and associates replicated the positive finding on rs41279104 (and also provided evidence for reduced NOS-I expression on the protein level in BA9 -part of the dorsolateral prefrontal cortex -for risk allele carriers), Okumura could not, although two other NOS1 SNPs were significant (but did not survive correction for multiple testing). The same was true for the study by Wang (Wang et al, 2012) in China, where a SNP in intron 2 of NOS1 was only nominally significant.…”