Genetic risk variants for schizophrenia have been linked to many related clinical and biological phenotypes with the hopes of delineating how individual variation across thousands of variants corresponds to the clinical and etiologic heterogeneity within schizophrenia. This has primarily been done using risk score profiling, which aggregates effects across all variants into a single predictor. While effective, this method lacks flexibility in certain domains: risk scores cannot capture nonlinear effects and do not employ any variable selection. We used random forest, an algorithm with this flexibility designed to maximize predictive power, to predict 6 cognitive endophenotypes in a combined sample of psychiatric patients and controls (N = 739) using 77 genetic variants strongly associated with schizophrenia. Tenfold cross-validation was applied to the discovery sample and models were externally validated in an independent sample of similar ancestry (N = 336). Linear approaches, including linear regression and task-specific polygenic risk scores, were employed for comparison. Random forest models for processing speed (P = .019) and visual memory (P = .036) and risk scores developed for verbal (P = .042) and working memory (P = .037) successfully generalized to an independent sample with similar predictive strength and error. As such, we suggest that both methods may be useful for mapping a limited set of predetermined, disease-associated SNPs to related phenotypes. Incorporating random forest and other more flexible algorithms into genotype-phenotype mapping inquiries could contribute to parsing heterogeneity within schizophrenia; such algorithms can perform as well as standard methods and can capture a more comprehensive set of potential relationships.

Genetic risk variants for schizophrenia have been linked to many related clinical and biological phenotypes with the hopes of delineating how individual variation across thousands of variants corresponds to the clinical and etiologic heterogeneity within schizophrenia. This has primarily been done using risk score profiling, which aggregates effects across all variants into a single predictor. While effective, this method lacks flexibility in certain domains: risk scores cannot capture nonlinear effects and do not employ any variable selection. We used random forest, an algorithm with this flexibility designed to maximize predictive power, to predict 6 cognitive endophenotypes in a combined sample of psychiatric patients and controls (N = 739) using 77 genetic variants strongly associated with schizophrenia. Tenfold cross-validation was applied to the discovery sample and models were externally validated in an independent sample of similar ancestry (N = 336). Linear approaches, including linear regression and task-specific polygenic risk scores, were employed for comparison. Random forest models for processing speed (P = .019) and visual memory (P = .036) and risk scores developed for verbal (P = .042) and working memory (P = .037) successfully generalized to an independent sample with similar predictive strength and error. As such, we suggest that both methods may be useful for mapping a limited set of predetermined, disease-associated SNPs to related phenotypes. Incorporating random forest and other more flexible algorithms into genotype-phenotype mapping inquiries could contribute to parsing heterogeneity within schizophrenia; such algorithms can perform as well as standard methods and can capture a more comprehensive set of potential relationships.

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.

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 non-converters 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. Here 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). Our cortical thinning classifier included nine microRNAs, p=3.63 × 10^-08, R²=0.358, permutation-based p=0.039, the gene targets of which were enriched for intracellular signaling pathways that are important to coordinating inflammatory responses within immune cells (p<0.05, Benjamini-Hochberg corrected). The classifier was also related to proinflammatory cytokine levels in serum (p=0.038). 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=0.03). 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.