精神分裂症之潛在生物標記探索：微小核醣核酸在周邊血液表現分析

Abstract

最近陸續有研究顯示周邊血液的基因表現某種程度可以區分精神分裂症疾病狀態，有潛力用來作為精神分裂症診斷的工具，但至目前為止周邊血液基因表現研究都局限於訊息核醣核酸 (mRNAs) 的探索。最近，微小核醣核酸 (microRNAs) 逐漸被證實是調控神經發育與功能的重要分子，或許周邊血液的微小核醣核酸表現剪影具有潛力發展為精神分裂症生物標記。本研究嘗試自周邊血液尋找特定的微小核醣核酸，發展精神分裂症之生物標記。研究擬自台大醫院收集20位精神分裂症病人與20位性別年齡配對的健康對照。利用ABI PRISM 7900即時反轉錄聚合酶連鎖反應 (real time RT-PCR) 方法測量365種人類微小核醣核酸的表現。我們使用監督性分類 (supervised classification)，並進行交叉驗證 (cross-validation) 來選擇具分類代表性的微小核醣核酸。接著使用生物資訊的方法，預測這些微小核醣核酸調控的基因群，以及生物功能。本研究定義6個微小核醣核酸標誌，可以將精神分裂症與健康對照區分 (準確率70-80%)。而這些微小核醣核酸標誌可能參與雌激素訊息傳導與多巴胺訊息傳導途徑，且與神經以及骨骼與肌肉發育與功能相關。結果顯示以血液中的全基因體微小核醣核酸表現剪影定義精神分裂症的生物標記是可行的，本研究定義的6個微小核醣核酸標誌將進行進一步探究。

Recently several studies have demonstrated the potential utility of the blood-based gene expression profiling as a diagnostic tool for schizophrenia, though these studies were limited to the expression of protein-coding genes. The expressions of non-coding genes such as microRNAs (miRNAs) are now considered to play a significant role for the regulation of gene expression by means of inhibiting the translation of messenger RNAs (mRNAs), indicating that the miRNAs profiling in the peripheral blood might be potential biomarkers for schizophrenia. This study aimed to identify blood-based miRNA signature and evaluate its potential as biomarkers for schizophrenia. The study enrolled 20 schizophrenia patients at National Taiwan University Hospital and 20 age- and gender-matched normal controls. The expressions of 368 human miRNAs in their peripheral blood were examined using ABI PRISM 7900 Real Time PCR system. Supervised classification with internal cross-validation method was used to identify miRNAs that might be useful as biomarkers for schizophrenia. Possible biological mechanisms implicated in the target genes involved by the miRNAs were explored using bioinformatic methods as well. We identified a blood-based six-miRNA signature that could discriminate schizophrenia patients from normal controls with an accuracy rate ranging from 70% to 80%. Bioinformatic analyses indicated that dysregulation of these miRNAs in peripheral blood might be involved in estrogen receptor and dopamine receptor signaling pathways in schizophrenia patients. Moreover, possible biological functions of the target genes regulated by the six miRNAs included nervous, skeletal, and muscular system development and function. We concluded that genome-wide miRNA profiling was a feasible way for the identification of biomarkers for schizophrenia and the six-miRNA signature identified in this study warrants further investigation.