UC San Diego

Abstract Background: In a recent report of the North American Prodrome Longitudinal Study (NAPLS), clinical high-risk individuals who converted to psychosis showed a steeper rate of cortical gray matter reduction compared with nonconverters and healthy controls, and the rate of cortical thinning was correlated with levels of proinflammatory cytokines at baseline. These findings suggest a critical role for microglia, the resident macrophages in the brain, in perturbations of cortical maturation processes associated with onset of psychosis. Elucidating gene expression pathways promoting microglial action prior to disease onset would inform potential preventative intervention targets. Methods: We used a forward stepwise regression algorithm to build a classifier of baseline microRNA expression in peripheral leukocytes associated with annualized rate of cortical thinning in a subsample of the NAPLS cohort (N = 74). Results: Our cortical thinning classifier included 9 microRNAs, P = 3.63 × 108, R2 = 0.358, permutation-based P = .039, the gene targets of which were enriched for intracellular signaling pathways that are important to coordinating inflammatory responses within immune cells (P < .05, Benjamini-Hochberg corrected). The classifier was also related to proinflammatory cytokine levels in serum (P = .038). Furthermore, miRNAs that predicted conversion status were found to do so in a manner partially mediated by rate of cortical thinning (point estimate = 0.078 [95% CIs: 0.003, 0.168], P = .03). Conclusion: Many of the miRNAs identified here have been previously implicated in brain development, synaptic plasticity, immune function, and/or schizophrenia, showing some convergence across studies and methodologies. Altered intracellular signaling within the immune system may interact with cortical maturation in individuals at high risk for schizophrenia promoting disease onset.