臺大精神疾病流行病學研究室 簡介

主持人:陳為堅教授

更新日期: 2018年9月17日

  本研究室的研究取向,基本上屬於精神流行病學與遺傳流行病學。而這兩種研究取向所聚焦的精神疾病或行為,則包括:(1) 思覺失調症 (舊稱精神分裂症) 及其內表型;(2) 物質使用與使用疾患。對於2009年之前的研究,可參考2009年的研究簡介一文。

(一) 思覺失調症 (schizophrenia)

  探討思覺失調症的致症機轉與生物標誌,長久以來都是本研究室的研究重心。這部分的研究都是與台大精神科胡海國教授團隊合作。

  早期我們透過家族研究,分別蒐集思覺失調症的單發型家庭 (sporadic or simplex families),與多發型家庭 (familial or multiplex families)。除了利用遺傳研究診斷問卷 (Diagnostic Interview for Genetic Studies, DIGS) 進行半結構式的精神訪談 (semi-structured psychiatric interview) 外,還測量了一列系的內表型 (endophenotype),包括 (1) 連續表現測驗 (Continuous Performance Test, CPT),測量持續注意力缺失 (sustained attention deficit); (2) 知覺失調性人格特質 (schizotypal personality),測量源自於神經系統的訊息處理能力出了問題,致使病人有認知與知覺缺失、人際缺失、與認知與行為的失序等特質; (3) 威斯康辛卡片分類測驗(Wisconsin Card Sorting Test, WCST),測量執行功能 (executive function) ; (4) 菸鹼酸皮膚貼片測試 (niacin skin patch test),測量因細胞膜脂質異常而呈現的紅腫反應變弱 (attenuated flush response to niacin patch)。

  在2000年以前,本研究室有關思覺失調症的遺傳標誌研究,以Taiwan Schizophrenia Linkage Study (TSLS, 1998 to 2002) 為代表。TSLS從全台灣之精神院所蒐集了607個思覺失調症同病手足之家庭,其中的557個家庭 (1207 罹病者與1035 未罹病者) 完成全基因體掃瞄 (368個微衛星遺傳標誌)。有關這個時期的一系列研究,可參考我寫的一篇回顧論文 (Chen WJ. Taiwan Schizophrenia Linkage Study: Lessons learned from endophenotype-based genome-wide linkage scans and perspective. Am J Med Genet B Neuropsychiatr Genet 2013;162B:636-647).

   進入全基因體關聯分析 (genome wide association studies, GWAS) 的時代後,我們執行另一個大型家庭計畫,稱為Schizophrenia-Trio Genomic Research of Taiwan (S-TOGET),全台蒐集3800名思覺失調症病人-雙親三元體 (trios) 資料。病人接受抽血及DIGS訪談及多種內表型測量,包括CPT, WCST, niacin skin test, craniofacial features等。透過加入Psychiatric Genomics Consortium (PGC),其中約有1700 個trios 完成PsychChip的GWAS基因定型,以及約640個trios完成exome sequencing。此外,我們也把TSLS的一部分家庭進行GWAS基因定型。為了讓TSLS也能與S-TOGET有同樣的PsychChip 資料,我們先在NHRI一個三年計畫支持下,完成200 個TSLS 家庭的PsychChip 基因定型,目前正在執行一個科技部三年計畫(2018.8-2021.7),預計把其餘的TSLS家庭也完成PsychChip 基因定型。

   此外,本研究室也從事複雜性疾病的基因表現研究。一開始是與肺癌研究團隊合作,發現可用基因表現偏差或微核糖核酸表現偏差來預測肺癌預後。接著,我們發現周邊血液的7個miRNA表現偏差,可辨識思覺失調症。進一步的追蹤研究,發現這7個miRNA的表現偏差,從急性發作到2個月後的部分緩解,都是穩定存在。在與墨爾本大學的Brain Dean 教授的合作,我們發現周邊血液中呈現表現偏差的miR-34a and miR-548d,在選定的二個大腦區域中並未發現。不過我們意外發現皮質區(BA46) 的miR-34a表現量隨年齡增加而增加,皮質下的尾核則無此象。而且這種相關在正常對照的關聯高於病人組。這顯示miRNA的調控異常、疾病易感受性的體質、與老化的關係值得進一步研究。

(二) 物質使用

  本研究室對於物質使用的研究,有二個焦點:酒精與非法藥物。在酒精方面,早期是聚焦於酒精使用疾患的研究,主要中研院生醫所鄭泰安教授合作。包括原住民不同族群之酒精使用疾患盛行率、發生率,以及酒精代謝基因變異對於精使用疾患的影響。後來則與陽明大學公衛所陳娟瑜教授合作,探討兒童青少年的飲酒行為及其相關因子。

   在非法藥物方面,本研究室早期先是探討不同的調查方法,比如:(1) 比較急診病患之自我陳報與尿液檢查結果,發現自我陳報至少有66.6-70.0% 的偽陰性。(2) 利用外展方式,發現有翹課經驗之青少年比?有翹課經驗者有較高之非法藥物使用經驗。(3) 以機分派方式,比較網路版問卷與傳統紙筆問卷,發現前者在敏感性題目有較高的陳報率。

   結合這些方法,我們執行了2004到2006年的全國青少年物質使用調查。利用這個調查資料,我們有一系列關於青少年非法藥物使用的年度趨勢以及物質使用之危險因子,包括打工經驗、第一次喝酒情境、與翹家經驗等。後來我們又執行了respondent-driven sampling (RDS) 的四年計畫,以社會網絡方式,蒐集將近1000位的菸酒使用者。結果顯示大約五分之的人曾經使用過非法藥物,其中的60%是多重藥物使用者。

   最近的研究,則是2014年的全國物質使用調查,針對12-64歲民眾,以分層多階段隨機抽樣方式,利用電腦輔助式自我訪談,讓民眾以匿名方式,完成填答問卷。最後完成17,837位民眾之問卷,完成率為62.2%。結果發現有1.29%的人曾經使用過法藥物。目前本研究室正在執行最新一波的2018年全國物質使用調查。

   另外,隨著政府巨量資料計畫推動,本研究室也負責其中的藥物濫用趨勢分析及前瞻性風險辨識。我們基本上把法務部資料與衛福部資料結合,進行藥物濫用趨勢及其不良健康後果。並利用動模擬的方式,預測相關風險。

Lab of Psychiatric & Genetic Epidemiology: Brief Introduction

Principal Investigator: Prof. Wei J. Chen

Updated: September 17, 2018

The research approach adopted by this lab includes psychiatric epidemiology and genetic epidemiology. Through these two approaches, this lab focuses on the following psychiatric disorders or behavioral problems: (1) schizophrenia and its endophenotypes; and (2) substance use and use disorders. A more detailed description about the research activities prior to 2009 is provided an introduction in 2009 (in Chinese).

(1) Schizophrenia

Search for etiological factors and biomarkers for schizophrenia has long been the main research focus of this lab. This part has been in collaboration with Prof. Hai-Gwo Hwu’s team at Department of Psychiatry, College of Medicine, NTU.

In the early phase, we conducted family studies of schizophrenia via collection of sporadic (or simplex) and familial (or multiplex) families of schizophrenia patients. In addition to conducting the Diagnostic Interview for Genetic Studies (DIGS), a semi-structured psychiatric interview, we also measured a series of endophenotypes, including (1) the Continuous Performance Test (CPT), measuring sustain attention deficit; (2) schizotypal personality, measuring personality traits that might stem from impairment in information processing that results in cognitive-perceptual deficits, interpersonal deficits, and disorganization of cognition and behavior; (3) Wisconsin Card Sorting Test (WCST), measuring impairment in executive function; and (4) niacin skin patch test, measuring attenuated flush response to the niacin patch.

Prior to 2000, this lab’s research on schizophrenia is exemplified by Taiwan Schizophrenia Linkage Study (TSLS, 1998 to 2002). TSLS recruited 607 families of sib-pairs co-affected with schizophrenia throughout the country, and 557 of them (1207 affected and 1035 unaffected) underwent genome-wide linkage scan using 386 microsatellite markers. A summary of research results during this period is provided in a review (Chen WJ. Taiwan Schizophrenia Linkage Study: Lessons learned from endophenotype-based genome-wide linkage scans and perspective. Am J Med Genet B Neuropsychiatr Genet 2013;162B:636-647).

Entering the era of genome wide association studies (GWAS), we conducted another large-scale family study of schizophrenia called Schizophrenia-Trio Genomic Research of Taiwan (S-TOGET). The project recruited 3800 schizophrenia patients and their healthy parents (trios). Patients and their parents were drawn for venous blood, which was sent to the US for establishing EB-virus transformed lymphoblastoid cell lines, and each patient underwent an interview using DIGS and measurements on CPT, WCST, niacin skin test, and craniofacial features. After joining Psychiatric Genomics Consortium, about 1700 trios have been genotyped for GWAS using PsychChip, and 640 of them further received exome sequencing. Now we are conducting GWAS genotyping using PsychChip for the families of TSLS. Supported by a 3-year NHRI project, 333 families (704 affected individuals and 585 unaffected individuals) have been genotyped using the PsychChip. Starting in 2018, a new 3-year MOST project (2018.8 – 2021.7) will continue to do the PsychChip genotyping for the remaining TSLS families. With the abundant GWAS data available, a series of polygenic risk score analyses are being conducted.

In addition, Prof. Chen’s lab has embarked on the gene expression research on complex diseases. Initially, his collaboration with lung cancer researchers led to the identification of biomarker signature for lung cancer using either mRNAs or microRNAs. Recently his team has identified a seven-microRNA signature as potential peripheral biomarkers for schizophrenia. The 7 miRNAs’ expression levels were later found to be stable from acute state to partial remission two months later among schizophrenia patients. In a collaboration with Prof. Brian Dean of University of Melbourne, we found the aberrant expression seen in the blood of miR-34a and miR-548d were not present in the brain samples. Unexpectedly, we found age-dependent increasing of miR-34a expressions in human cortical region (BA46) but not in subcortical region (caudate putamen). The correlation between miR-34a expression level in BA46 and age was much stronger in the controls than in the cases, and the corresponding correlation in the blood was only seen in the cases. The association between the miRNA dysregulations, the disease predisposition and aging warrants further investigation.

(2) Substance use

There have been two major themes in our research on substance use: alcohol and illicit drugs.

Regarding alcohol use, our early research was focused on alcohol use disorders, mainly collaborated with Prof. Andrew Cheng of Institute of Biomedical Research, Academia Sinica. The topics in this period included prevalence and incidence of alcohol use disorders, and the influence of the variants in alcohol-metabolizing genes on alcohol use disorder. More recently, we collaborated with Prof. Chuan-Yu Chen of Institute of Public Health, National Yang Ming University on alcohol use among children and adolescents.

Regarding illicit drug use, our early research was focused on the methodological evaluation, including (1) comparing the self-report versus urinalysis of illicit drug use among patients at emergency department, with a 66.6-70.0% of false negative rate; (2) recruiting adolescents via outreach, with an increased prevalence of illicit drug use among adolescents with truancy compared to those without truancy; (3) a randomized trial comparing web-based questionnaire versus paper-and-pencil questionnaire, with the former having an increased self-report rate about sensitive behavior.  

Incorporating those methodologies, we conducted the two-armed National Survey of Adolescent Substance Use from 2014 to 2016. Based on those surveys, we have published several papers on the trend of illicit drug use and its correlates, including employment, context of first alcohol drinking, and running away from home. Then we conducted respondent-driven sampling (RDS) of about 1000 alcohol- and tobacco-using young adults for 4 years. We found nearly one-fifth of the participants had ever used illegal drugs, of whom over 60% were polydrug users.

More recently, Prof. Chen’s team conducted the 2014 National Survey of Substance Use targeting Taiwanese civilians aged 12-64 years, using stratified, multi-stage, random sampling throughout the country. Totally 17,837 participants, a completion rate of 62.2%, completed a computer-assisted self-interview on tablet computers. Approximately 1.29% of respondents reported ever using any illicit drug once in their lifetimes. Currently Prof. Chen’s team is conducting the 2018 National Survey of Substance Use.

In addition, following the creation and promotion of government big data, we are conducting research on the trend of illicit drug use and their adverse health outcome via integrated data bases from Ministry of Justice and Ministry of Health and Welfare. We are also applying dynamic systems to model the incarcerated first-time drug offenders.