The SIGMAR1 gene is associated with a risk of schizophrenia and activation of the prefrontal cortex

Several studies have identified the possible involvement of sigma non-opioid intracellular receptor 1 (SIGMAR1) in the pathogenesis of schizophrenia. The Gln2Pro polymorphism in the SIGMAR1 gene has been extensively examined for an association with schizophrenia. However, findings across multiple studies have been inconsistent. We performed a meta-analysis of the association between the functional Gln2Pro polymorphism and schizophrenia using combined samples (1254 patients with schizophrenia and 1574 healthy controls) from previously published studies and our own additional samples (478 patients and 631 controls). We then used near-infrared spectroscopy to analyze the effects of the Gln2Pro genotype, a schizophrenia diagnosis and the interaction between genotype and diagnosis on activation of the prefrontal cortex (PFC) during a verbal fluency task (127 patients and 216 controls). The meta-analysis provided evidence of an association between Gln2Pro and schizophrenia without heterogeneity across studies (odds ratio = 1.12, p = 0.047). Consistent with previous studies, patients with schizophrenia showed lower bilateral activation of the PFC when compared to controls (p < 0.05). We provide evidence that Pro carriers, who are more common among patients with schizophrenia, have significantly lower activation of the right PFC compared to subjects with the Gln/Gln genotype (p = 0.013). These data suggest that the SIGMAR1 polymorphism is associated with an increased risk of schizophrenia and differential activation of the PFC.