一、背景
早發型思覺失調症有較嚴重的疾病症狀與較明顯的遺傳傾向。而微型核醣核酸包含遺傳與表觀遺傳之角色，並被認為是神經發展中主要調控因子之一，且可能被不同病程所影響。先前研究指出，微型核醣核酸的表現量可能導致神經發展的變化，進而與精神疾病的發病年齡相關。然而，對於與神經發展相關之微型核醣核酸(如:miR-137、miR-34a、miR-34b與miR-34c)與其於不同發病年齡的思覺失調症之神經發展過程表現程度仍未明確。本研究將探究miR-137、miR-34家族之異常表現量輔以神經發展標記測量，是否能作為不同發病年齡之潛在診斷生物標記。

二、實驗設計
本研究自台灣南部蒐集215名思覺失調症患者、40名躁鬱症患者、思覺失調症患者之一等親屬(早發型患者之親屬48名；成人型患者之親屬82名)與100名非精神疾病對照組的周邊血液，進行微型核醣核酸表現偵測。首先，將針對不同發病年齡之思覺失調症以及伴隨神經發展標記者，做miR-137、miR-34家族之表現量做分析。另外，我們也會透過分子功能集富集分析，探討思覺失調症患者之miR-137、miR-34家族於神經發展過程中，所共同牽涉之基因網絡。

三、結果
MiR-137、miR-34a所呈現的表現量在思覺失調症患者與躁鬱症患者(p < 0.001)有顯著差異，且此標記在精神疾病中可能與思覺失調症相關。同時，miR-137在思覺失調症患者與非精神疾病對照組(p < 0.001)也有差異。此外，miR-137、miR-34a與miR-34b在早發型和成人型思覺失調症患者之間有顯著差異(p < 0.005)。且在ROC曲線分析中，miR-34b有較佳的鑑別能力(AUC = 0.810)。進一步研究也發現，miR-137的表現量在早發型思覺失調症且有神經發展標記特徵之個案，相對於非精神疾病對照組有較高之鑑別能力(AUC = 0.910 - 0.957)。

四、結論
於周邊血液當中，三個候選的微型核醣核酸(miR-137、miR-34a與miR-34b)之異常表現能於早發型及成人型思覺失調症患者之間有差別。其可能隱含對於依賴微型核醣核酸調控之基因有異常表現，並可能透過其相關之表現數量性狀基因座所調變，進而同時增加思覺失調症不同發病之風險。本篇研究提供更進一步線索，有關於周邊血液之微型核醣核酸表現量結合神經發展測量，以作為神經發展狀態改變與發病年齡潛在穩定之生化標記。

Background.
The onset age of schizophrenia is related to the severity of the subsequent symptoms, especially the early-onset schizophrenia (EOS) could also reflect genetic propensity. MicroRNA (miRNA) can be regarded as one of the master regulators of neurodevelopment which displays genetic and epigenetic roles that could, therefore, be affected by disease processes. Previous studies have shown that miRNA expression for mental illness might manifest to alter neurodevelopment prior to disease onset. However, the neurodevelopment-related miRNAs (i.e. miR-137, miR-34a, miR-34b and miR-34c) expression levels in different age onset of schizophrenia during neurodevelopmental process remain unknown. In this study, we aimed to investigate the aberrant expression of miR-137 and miR-34 family combined with neurodevelopmental measures might serve as a clinically useful biomarker in different age onset of schizophrenia.

Experimental Design.
In the current study, we collected blood samples of patients with schizophrenia (n = 215), bipolar disorder patients (n = 40), nonpsychotic first-degree relatives (relatives of EOS, n = 48; relatives of AOS, n = 82) and nonpsychotic controls (n = 100) as comparison groups from southern Taiwan. First, we examined the miR-137 and miR-34 family expression levels in different age onset of schizophrenia with neurodevelopmental measures. On the other hand, we will identify miR-137 and miR-34 family target genes involved in neurodevelopment via functional enrichment analysis.

Results.
Mir-137 and miR-34a presented significant expression patterns that could distinguish schizophrenia patients from bipolar disorder (p < 0.001) and might specifically recognize schizophrenia patients from other mental illness. Meanwhile, miR-137 and miR-34a have also presented a significant difference between schizophrenia patients and nonpsychotic controls (p < 0.001). Furthermore, the expression levels of miR-137, miR-34a and miR-34b could appraise early-onset and adult-onset schizophrenia significantly (p < 0.005). However, in the ROC curve analysis, only miR-34b provided fine discriminant ability (AUC = 0.810). For the further examination, when the EOS with neurodevelopmental markers, the miR-137 expression levels would have significantly higher AUCs for differentiation (for EOS with NSS, AUC = 0.957; for EOS with MPA, AUC = 0.910).

Conclusions.
The aberrant expressions are seen in the peripheral blood of three candidate miRNAs (miR-137 and miR-34a and miR-34b) between EOS and AOS. This may suggest that abnormal regulation of miRNA-dependent gene expression may be modulated via their associated expression quantitative trait loci (eQTLs) and together increase the risk of different age at onset schizophrenia susceptibility. These findings provide further insights into peripheral miRNAs expression levels combined with neurodevelopmental measures as potential stable biomarkers for the alter neurodevelopmental status to disease onset.

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