Evidence for a Role of the <i>NOS1AP (CAPON)</i> Gene in Schizophrenia and Its Clinical Dimensions: An Association Study in a South American Population Isolate

Abstract

Background/Aims: Recent studies have implicated a region on chromosome 1q21-23, including the NOS1AP gene, in susceptibility to schizophrenia. However, replication studies have been inconsistent, a fact that could partly relate to the marked psychopathological heterogeneity of schizophrenia. The aim of this study is to evaluate association of polymorphisms in the NOS1AP gene region to schizophrenia, in patients from a South American population isolate, and to assess if these variants are associated with specific clinical dimensions of the disorder. Methods: We genotyped 24 densely spaced SNPs in the NOS1AP gene region in a schizophrenia trio sample. The transmission disequilibrium test (TDT) was applied to single marker and haplotype data. Association to clinical dimensions (identified by factor analysis) was evaluated using a quantitative transmission disequilibrium test (QTDT). Results: We found significant association between eight SNPs in the NOS1AP gene region to schizophrenia (minimum p value = 0.004). The QTDT analysis of clinical dimensions revealed an association to a dimension consisting mainly of negative symptoms (minimum p value 0.001). Conclusions: Our findings are consistent with a role for NOS1AP in susceptibility to schizophrenia, especially for the ‘negative syndrome’ of the disorder.

Identification of a Schizophrenia-Associated Functional Noncoding Variant in NOS1AP

“…We previously tested markers from this region for evidence of LD to schizophrenia in our Canadian families, identifying significant LD with three markers within the gene for NOS1AP (nitric oxide synthase 1 [neuronal] adaptor protein; formerly known as CAPON) (11). The same allele for two of these markers was recently reported to be associated in a South American population isolate (12). Association of different single nucleotide polymorphisms (SNPs) within NOS1AP to schizophrenia also has been reported in a Han Chinese sample (13).…”

Plasma nitrite/nitrate concentrations in patients with schizophrenia

“…NOS1 is highly expressed in the brain as well as in the airways, intestine, kidney and heart. Recently, Kremeyer et al (28) found a significant association between eight single nucleotide polymorphisms (SNPs) in the NOS1AP gene region and schizophrenia. Others (29) have shown that some SNPs in schizophrenics were characterized by increased gene expression leading to higher NO production.…”

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

“…To this end, a Pub Med search was carried out using the keywords "(NOS1AP OR CAPON) AND schizophrenia" as well as "NOS1 AND schizophrenia", to identify all genetic studies on NOS1AP (n=24 retrieved studies) or NOS1 (n=42 retrieved) and schizophrenic disorders. 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.…”

“…Following up the studies of Brzustowicz and colleagues, both positive (Kremeyer et al, 2009;Miranda et al, 2006;Zheng et al, 2005) as well as negative Nicodemus et al, 2010;Nicodemus et al, 2008) family-based and case-control studies were published. In addition, a mutation analysis suggested that rare coding variants in NOS1AP underlie obsessive-compulsive disorder and autism (Delorme et al, 2010).…”