NR3C1 and NR3C2 Genes Increase the Risk of Suicide Attempt in Psychiatric Disorder Patients with History of Childhood Trauma

BACKGROUND: Hypothalamic-pituitary-adrenal axis gene variants and childhood trauma (CT) are considered risk factors for suicide attempt (SA). The aim of the present study was analyzed gene x environment (GxE) interaction of NR3C1, NR3C2, and CT, and NR3C1 and NR3C2 gene expression in the development of SA with CT. PARTICIPANTS AND METHODS: A total of 516 psychiatric Mexican patients from Instituto Nacional de Psiquiatría Ramón de la Fuente Muñiz. Among them, 274 had SA at least once and 242 had not SA. Genetic variants of NR3C1 and NR3C2 were genotyped in all the patients, of which were obtained the CT information from medical records. Additionally, the gene expression of NR3C1 and NR3C2 was also analyzed for a subsample of 96 patients, obtaining the TC information from Childhood Trauma Questionnaire (CTQ). RESULTS: The analysis showed a GxE interaction of NR3C1, NR3C2, and CT (OR=2.8, 95% CI [1.9–3.9], p<0.0001). Interactions were also observed with neglect (OR=2.1, 95% CI [1.4–3.1], p<0.0001), emotional abuse (OR=2.1, 95% CI [1.5–3], p<0.0001), and sexual abuse (OR=2.4, 95% CI [1.4–2.9], p<0.0001) in the prediction of SA. The analysis of gene expression identified an overexpression of NR3C1 in SA patients with high scores for physical and sexual abuse (p<0.0001; p<0.0006, respectively) and emotional neglect (p=0.014). An underexpression was observed of NR3C2, associated with high scores of trauma subtypes (p<0.0001) except physical neglect. Additionally, we observed an overexpression of NR3C1 gene in patients with SA carriers of A allele of rs6191 (p=0.0015). Also, overexpression of NR3C1 gene in carriers of G allele of rs6198 and underexpression of NR3C2 gene in carriers of G allele of rs5522 (p<0.0001). CONCLUSION: Our findings suggest that genetic variants of NR3C1 and NR3C2 differentially affect expression levels, increasing the susceptibility to SA in psychiatric patients with a history of CT.