Abstract
Epigenetic dysregulation is thought to contribute to the etiology of schizophrenia (SZ), but the cell type-specificity of DNA methylation makes population-based epigenetic studies of SZ challenging. To train an SZ case–control classifier based on DNA methylation in blood, therefore, we focused on human genomic regions of systemic interindividual epigenetic variation (CoRSIVs), a subset of which are represented on the Illumina Human Methylation 450K (HM450) array. HM450 DNA methylation data on whole blood of 414 SZ cases and 433 non-psychiatric controls were used as training data for a classification algorithm with built-in feature selection, sparse partial least squares discriminate analysis (SPLS-DA); application of SPLS-DA to HM450 data has not been previously reported. Using the first two SPLS-DA dimensions we calculated a “risk distance” to identify individuals with the highest probability of SZ. The model was then evaluated on an independent HM450 data set on 353 SZ cases and 322 non-psychiatric controls. Our CoRSIV-based model classified 303 individuals as cases with a positive predictive value (PPV) of 80%, far surpassing the performance of a model based on polygenic risk score (PRS). Importantly, risk distance (based on CoRSIV methylation) was not associated with medication use, arguing against reverse causality. Risk distance and PRS were positively correlated (Pearson r = 0.28, P = 1.28 × 10−12), and mediational analysis suggested that genetic effects on SZ are partially mediated by altered methylation at CoRSIVs. Our results indicate two innate dimensions of SZ risk: one based on genetic, and the other on systemic epigenetic variants.
Highlights
Schizophrenia (SZ), a neurodevelopmental disorder affecting 1% of the world’s population, is characterized by hallucinations, delusion, and cognitive deficits [1]
Additive effects of these variants enabled the development of a polygenic risk score (PRS) to quantify genetic predisposition for SZ [1, 7], a classifier for SZ case–control status based on PRS performed poorly [9]
At CoRSIV probes, DNA methylation is generally positively correlated between blood and brain Our focus on CoRSIVs is based on the rationale that, at these regions, methylation measurements in blood yield information about epigenetic regulation in the brain
Summary
Schizophrenia (SZ), a neurodevelopmental disorder affecting 1% of the world’s population, is characterized by hallucinations, delusion, and cognitive deficits [1]. Additive effects of these variants enabled the development of a polygenic risk score (PRS) to quantify genetic predisposition for SZ [1, 7], a classifier for SZ case–control status based on PRS performed poorly (area under the receiver operating characteristic curve, AUROC = 0.58–0.70) [9]. Together, these observations led to speculation that, in addition to genetic and environmental factors, epigenetic mechanisms may play an important role in the etiology of SZ [3]. Each of the 9926 CoRSIVs identified is statistically significant (P < 0.05), Received: 31 May 2021 Revised: 7 June 2021 Accepted: 22 June 2021
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