Genetic Associations and Interactions Between the NR3C1 (GR) and NR3C2 (MR) Genes in Schizophrenia.

OBJECTIVE: Glucocorticoid receptor (GR, encoded by NR3C1) and mineralocorticoid receptor (MR, encoded by NR3C2) are critical regulators of the hypothalamic-pituitary-adrenal (HPA) axis and stress response, both of which are closely related to the pathogenesis of schizophrenia. This study aimed to investigate the genetic associations and gene-gene interactions of NR3C1 and NR3C2 polymorphisms with schizophrenia. METHODS: A total of 527 participants (162 schizophrenia patients and 365 healthy controls) were initially enrolled. Given the insufficient sample size of female subjects, additional participants were recruited using identical diagnostic and enrolment criteria, yielding a final expanded cohort of 279 patients and 502 healthy controls (n = 781) for validation of the NR3C1 rs6191 locus. Five single nucleotide polymorphisms (SNPs) of NR3C1 (rs6191, rs6198, rs6190, rs56149945 and rs41423247) and four SNPs of NR3C2 (rs2871, rs5522, rs5525 and rs2070951) were genotyped via an improved multiplex ligation detection reaction (iMLDR) assay. RESULTS: In the expanded sample, the NR3C1 rs6191 polymorphism was significantly associated with schizophrenia in females. Females harbouring the CC genotype at rs6191 exhibited a higher risk of schizophrenia than those carrying the AA or AC genotypes. No significant between-group differences were observed in the allele or genotype frequencies of the four NR3C2 SNPs. Notably, significant gene-gene interactions were detected between NR3C1 and NR3C2 loci, with the rs6191/rs5522/rs2871 combination identified as the optimal model (cross-validation consistency = 10/10). CONCLUSION: Our findings support NR3C1 as a candidate susceptibility gene for schizophrenia. The NR3C1 rs6191 polymorphism (3'-UTR region) is associated with schizophrenia in the female population, and the CC genotype at this locus confers an elevated risk of schizophrenia. Whereas NR3C2 polymorphisms are not independently associated with schizophrenia, significant gene-gene interactions exist between NR3C1 and NR3C2 loci.