Stress, Cortisol and NR3C1 in At-Risk Individuals for Psychosis: A Mendelian Randomization Study

Introduction The emergence of psychosis in at-risk individuals results from interactions between genetic vulnerability and environmental factors, possibly involving dysregulation of the hypothalamic-pituitary-adrenal axis. Hypercorticism was indeed described in schizophrenia and ultra-high-risk states, but its association with clinical outcome has yet to be demonstrated. The impact of stress through cortisol may vary depending on the expression level of genes related to the stress pathway. Methods To test this hypothesis, we selectedNR3C1, the gene encoding the glucocorticoid receptor, and modeled through logistic regression how its peripheral expression could explain some of the risk of psychosis, independently of peripheral cortisol levels, in a French longitudinal prospective cohort of 133 at-risk individuals, adjusted for sex, age, cannabis, and antipsychotic medication intake. We then performed a genome-wide association analysis, stratified by sex (55 females and 78 males), to identifyNR3C1expression quantitative trait loci to be used as instrumental variables in a Mendelian randomization framework. Results NR3C1expression was significantly associated with a higher risk of conversion to psychosis (OR = 2.03, p = 0.03), independently of any other factor. Cortisol was not associated with outcome nor correlated withNR3C1. In the female subgroup, rs6849528 was associated both withNR3C1mRNA levels (p = 0.015, Effect-Size = 2.7) and conversion (OR = 8.24, p = 0.03). Conclusions For the same level of cortisol,NR3C1expression increases psychotic risk, independently of sex, age, cannabis, and antipsychotic intake. In females, Mendelian randomization confirmedNR3C1's effect on outcome to be unbiased by any environmental confounder.