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Context: NRG1 is a schizophrenia candidate gene and plays an important role in brain development and neural function. Schizophrenia is a complex disorder, with etiology likely due to epistasis., Objective: To examine epistasis between NRG1 and selected N-methyl-d-aspartate-glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, and NOS1AP., Design: Schizophrenia case-control sample analyzed using machine learning algorithms and logistic regression with follow-up using neuroimaging on an independent sample of healthy controls., Participants: A referred sample of schizophrenic patients (n = 296) meeting DSM-IV criteria for schizophrenia spectrum disorder and a volunteer sample of controls for case-control comparison (n = 365) and a separate volunteer sample of controls for neuroimaging (n = 172)., Main Outcome Measures: Epistatic association between single-nucleotide polymorphisms (SNPs) and case-control status; epistatic association between SNPs and the blood oxygen level-dependent physiological response during working memory measured by functional magnetic resonance imaging., Results: We observed interaction between NRG1 5' and 3' SNPs rs4560751 and rs3802160 (likelihood ratio test P = .00020) and schizophrenia, which was validated using functional magnetic resonance imaging of working memory in healthy controls; carriers of risk-associated genotypes showed inefficient processing in the dorsolateral prefrontal cortex (P = .015, familywise error corrected). We observed epistasis between NRG1 (rs10503929; Thr286/289/294Met) and its receptor ERBB4 (rs1026882; likelihood ratio test P = .035); a 3-way interaction with these 2 SNPs and AKT1 (rs2494734) was also observed (odds ratio, 27.13; 95% confidence interval, 3.30-223.03; likelihood ratio test P = .042). These same 2- and 3-way interactions were further biologically validated via functional magnetic resonance imaging: healthy individuals carrying risk genotypes for NRG1 and ERBB4, or these 2 together with AKT1, were disproportionately less efficient in dorsolateral prefrontal cortex processing. Lower-level interactions were not observed between NRG1 /ERBB4 and AKT1 in association or neuroimaging, consistent with biological evidence that NRG1 × ERBB4 interaction modulates downstream AKT1 signaling., Conclusion: Our data suggest complex epistatic effects implicating an NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia.

Genetic variants in GPR85 (SREB2: rs56080411 and rs56039557) have been associated with risk for schizophrenia. Here, we test the hypothesis that these variants impact on brain function in normal subjects, measured with functional magnetic resonance imaging (fMRI) paradigms that target regions with greatest SREB2 expression (hippocampal formation and amygdaloid complex). During a facial emotion recognition paradigm, a significant interaction of rs56080411 genotype by sex was found in the left amygdaloid complex (male risk allele carriers showed less activation than male homozygotes for the non-risk allele, while females showed the opposite pattern). During aversive encoding of an emotional memory paradigm, we found that risk allele carriers for rs56080411 had greater activation in the right inferior frontal gyrus. Trends in the same direction were present for rs56039557 in the right occipital cortex and right fusiform gyrus. During a working memory paradigm, a significant sex-by-genotype interaction was found with male risk allele carriers of rs56080411 having inefficient activation within the left dorsolateral prefrontal cortex (DLPFC), compared with same sex non-risk carriers, while females revealed an opposite pattern, despite similar levels of performance. These data suggest that risk-associated variants in SREB2 are associated with phenotypes similar to those found in patients with schizophrenia in the DLPFC and the amygdala of males, while the pattern is opposite in females. The findings in females and during the emotional memory paradigm are consistent with modulation by SREB2 of brain circuitries implicated in mood regulation and may be relevant to neuropsychiatric conditions other than schizophrenia. [ABSTRACT FROM AUTHOR]