Neurodevelopment regulators miR-137 and miR-34 family as biomarkers for early and adult onset schizophrenia

Bao-Yu Chen,Fong-Lin Jang,Hung-Pin Tan,Jin-Jia Lin,Ming-Kun Lu,Sheng-Hsiang Lin

doi:10.1038/s41537-021-00164-1

Abstract

Early-onset schizophrenia (EOS) may have stronger familial aggregation and a more severe outcome than adult-onset schizophrenia (AOS). MicroRNA (miRNA) takes on dual roles as a genetic and epigenetic modulator, which may mediate the influence of genetic risk. Neurological soft signs (NSS) are neurological abnormalities that may be intermediate phenotypes or endophenotypes for schizophrenia. Our previous study found poorer performance on NSS tests from patients with EOS and their unaffected first-degree relatives. Thus, we aimed to identify a set of aberrant neurodevelopmental-related miRNAs that could serve as potential biomarkers for EOS or schizophrenia with NSS. This study included 215 schizophrenia patients (104 EOS and 111 AOS), 72 unaffected first-degree relatives, 31 patients with bipolar disorder, and 100 healthy controls. Differential expression analysis revealed that miR-137, miR-34b, and miR-34c were significantly up-regulated in patients with schizophrenia and their unaffected first-degree relatives compared to healthy controls. Receiver operating characteristic (ROC) analysis showed that the miR-137 expression signature could be used to discriminate between patients with EOS and healthy controls (AUC = 0.911). Additionally, miR-34b had the highest ability to discriminate between EOS and AOS (AUC = 0.810), which may indicate different aetiological pathways to disease onset. Moreover, miR-137 dysregulation was correlated with almost all NSS subscales (i.e., sensory integration, motor sequencing, etc.) and, when EOS patients with NSS, miR-137 expression discriminated these patients from healthy controls to a greater extent (AUC = 0.957). These findings support the potential for neurodevelopmental-related miRNAs to be used as indicators of vulnerability to EOS.

Highlights

Schizophrenia (SZ) is a severe chronic mental disorder with a wide range of symptoms characterized by neurocognitive and neurodevelopment impairments, and when a diagnosis is made during late adolescence or early adulthood, genetic predisposition plays a large role[1]
Previous studies indicate that Early-onset schizophrenia (EOS) and adultonset schizophrenia (AOS) may share similar pathophysiologic features, but EOS may reflect a more severe form of the disease that is associated with a greater genetic predisposition[7,8]
There were no differences in age between the patients with SZ, patients with bipolar disorder, or healthy controls

Summary

Introduction

Schizophrenia (SZ) is a severe chronic mental disorder with a wide range of symptoms characterized by neurocognitive and neurodevelopment impairments, and when a diagnosis is made during late adolescence or early adulthood, genetic predisposition plays a large role[1]. Previous studies indicate that EOS and adultonset schizophrenia (AOS) may share similar pathophysiologic features, but EOS may reflect a more severe form of the disease that is associated with a greater genetic predisposition[7,8]. Aberrant miRNA expression may generate abnormal epigenetic patterns or distant regulatory elements, which may contribute to the dysregulation of critical genes involved in modulating the age of onset of SZ. The largest GWAS meta-analysis of SZ to date, which systematically characterized the most important miRNAs associated with neurodevelopment and synaptic transmission, identified miR-137 in its target gene set[16]. The dysregulation of miR-34a has been linked to neuronal development, which might provide critically needed insight into the pathogenesis of partial psychosis symptoms[17]

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