精神分裂症之基因體學： 疾病成因與藥物療效相關基因之探討

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精神分裂症之基因體學：疾病成因與藥物療效相關基因之探討

Genomic Study of Schizophrenia: Susceptibility and Treatment Outcome-Related Genes

陳芝宇 , Masters　　Advisor：許明志　　Co-advisor ：洪靚娟

繁體中文

精神分裂症；基因多型性；藥物基因體學； Risperidone ；體重增加； schizophrenia ； genetic polymorphism ； pharmacogenomics ； Risperidone ； weight-gain

Abstract │ Reference (451) │ Altmetrics

Abstract 〈TOP〉

精神分裂症是嚴重的精神疾病，會造成思考、認知、行為及情感等多方面的障礙。目前對於精神分裂症的病因仍未有明確的發現，但許多研究指出，環境及基因因素在精神分裂症的形成上扮演著重要的角色。精神分裂症的罹病風險在一般人大約為0.6到1.9%，但在一等親患有精神分裂症的個體上，罹病風險高達10%，由此可知基因因素確實影響著精神分裂症的發生。目前精神分裂症的治療以藥物治療為主。第一代抗精神分裂症藥物主要作用於多巴胺受體，阻礙多巴胺徑路的傳遞。第一代抗精神分裂症藥物可改善精神分裂症的正向症狀，但對負向症狀卻無法發揮作用，並且由於其在多巴胺受體的作用，第一代抗精神分裂症藥物易引起錐體外副作用。1990年代後期，許多第二代抗精神分裂症藥物問世，第二代抗精神分裂症藥物對於負向症狀有良好的改善效果，也較不容易引起錐體外副作用，其中，Risperidone是最廣為被使用的第二代抗精神分裂症藥物。但並非所有的患者對於第二代抗精神分裂症藥物都有治療反應，約有三分之一的患者對藥物治療反應不佳，此外，雖然第二代抗精神分裂症藥物相較於第一代抗精神分裂症藥物較不易引起錐體外副作用，但在許多使用第二代抗精神分裂症藥物的患者身上常觀察到體重增加的情形。

由於精神分裂症罹病風險和基因的相關性以及過去許多研究發現單核苷酸基因多型性和第二代抗精神分裂症藥物治療效果及所引起之體重增加間的關係，本研究致力於尋找和精神分裂症罹病風險及Risperidone療效及所引起之體重增加有關之單核苷酸基因多型性位點，以期未來可應用於臨床治療決策上。

本研究分為三部分，第一部分為探討和精神分裂症相關之基因，以及其基因上之基因多型性和精神分裂症罹病風險間的相關性；第二部分就第二代抗精神病藥物Risperidone進行相關之基因多型性和治療效果間相關性的分析；第三部分則針對Risperidone所引起之體重增加進行基因多型性的相關性研究。

本研究共納入台灣住院精神分裂症患者114人與健康受試者100人，並利用PCR-RFLP (Polymerase Chain Reaction–Restriction Fragment Length Polymorphism)方法與Real-time PCR方法進行49個位點的基因型鑑定。所納入的基因包含ABCB1、ABCC2、ANKK1、BDNF、COMT、CYP3A5、DRD1、DRD2、DRD3、HRH3、HTR1A、HTR1B、HTR2A、HTR3A、HTR6、MC4R、TPH1、TRPM1與SLC25A27等19個基因。
	
在致病相關方面發現多巴胺受體基因DRD2上的位點rs4648317與rs1799978、HTR2A上的rs2296973、HRH3上的位點rs3787429與TRPM1上的位點rs12901022皆與精神分裂症的罹病相關，且其相關性經校正後仍達顯著水準。這些結果顯示精神分裂症的罹病風險主要受到調控多巴胺D2受體與血清素5-HT2A受體基因的影響，同時，影響多種神經傳遞物質釋放的組織胺H3受體之基因上的變異也與精神分裂症之罹病風險有關。由全基因組關連性掃描研究發現的TRPM1上之變異與精神分裂症間的相關性則是在本研究中首次被證實。

在Risperidone的治療效果方面，屬於血清素受體家族的5-HT1A受體基因上的位點rs10042486被發現和患者使用Risperidone治療後的PANSS量表總分改變百分比具有相關性，且經過Hochberg多重比較後仍有統計上顯著相關 (p=0.0004)。在PANSS量表各次量表的分析中，並無發現單點的顯著性，然而在回歸模型中卻發現Risperidone對各項症狀的改善主要受到多巴胺D2受體與血清素5-HT2A受體基因上變異所影響。

本研究的第三部分為Risperidone所引起的體重改變。研究中以BMI增加7%為切點，將使用Risperidone的患者分為BMI顯著增加組與未顯著增加組，經過分析後雖無發現單點間與Risperidone引起的體重增加有相關性，但回歸模型中發現患者治療後的BMI受到HTR3A rs1062613、ABCB1 rs2032582、HTR1A rs878567等位點的影響，顯示治療後的BMI受多重的位點共同影響。
	
根據本研究結果，精神分裂症與其治療效果主要受多巴胺與血清素受體相關基因上的變異所影響。未來若能進一步證實本研究中的發現，或許能提供臨床執業人員精神分裂症診斷及治療選擇的參考。

Parallel Abstract 〈TOP〉

Schizophrenia is a devastating mental disease which influences thought processes and emotional responsiveness. Although the etiology of schizophrenia is unknown, it is commonly considered to be an environmentally and genetically mediated mental disorder. The risk of developing schizophrenia is about 0.6-0.9% in general population; however, the risk rises to 10% in someone who has a first-degree relative with schizophrenia. This suggests a strong genetic basis for schizophrenia. The mainstay of treatment in schizophrenia is pharmacotherapy. First-generation antipsychotics relieve positive symptoms of schizophrenia through intercepting dopamine pathway in brain by blocking on dopamine receptors. First-generation antipsychotics have only a limited effect on negative symptoms of schizophrenia and are more likely to cause extrapyramidal side effects. In contrast with first-generation antipsychotics, second-generation antipsychotics are less likely to cause extrapyramidal side effects and are more effective on negative symptoms. Among all the second-generation antipsychotics, Risperidone is the mostly prescribed antipsychotics to date. It’s has been observed that not all schizophrenia patients respond to the same antipsychotics equally. Besides, although second-generation antipsychotics are less likely to cause extrapyramidal side effects, weight gain after treated with second-generation antipsychotics is also observed.

Several previous studies have found the relationships between genetic polymorphisms and schizophrenia. Antipsychotic response and drug-induced side effects have also been found to associate with genetic polymorphisms. Therefore, this present study dedicates to find how single nucleotide polymorphisms involve in schizophrenia susceptibility and treatment response of Risperidone and weight gain.

This study is composed of 3 parts. First part is about the schizophrenia susceptibility and it related gene and genetic polymorphisms. The second part investigates the relationships between response of Risperidone and related single nucleotide polymorphisms. Risperidone induced weight gain and the association with single nucleotide polymorphisms are discussed in the third part.

There were 114 inpatients with schizophrenia recruited in this study. We also included 100 subjects without mental diseases as healthy control. PCR-RFLP (Polymerase Chain Reaction–Restriction Fragment Length Polymorphism) and Real-time PCR were performed to determine the genotypes of 49 SNP (single-nucleotide polymorphism) on 19 genes. Target genes in this study are ABCB1、ABCC2、ANKK1、BDNF、COMT、CYP3A5、DRD1、DRD2、DRD3、HRH3、HTR1A、HTR1B、HTR2A、HTR3A、HTR6、MC4R、TPH1、TRPM1 and SLC25A27.

Within the 49 SNP, rs4648317 and rs1799978 on DRD2, rs2296973 on HTR2A, rs3787429 on HRH3 and rs12901022 on TRPM1 were found to be associated with schizophrenia susceptibility, and these results remained significant after correction. This indicates that the main risk genes of schizophrenia may be genes encode for dopamine and serotonin receptors, also, the polymorphisms on gene encodes for histamine H3 receptor which regulates many neurotransmitters in central nervous system may influence risk for schizophrenia. We also found that polymorphisms on TRPM1 were related to schizophrenia susceptibility, too. This gene was proved to have association with response of Risperidone in a GWAS (Genome-wide association studies) in 2011.

For the response of Risperidone, rs10042486 on HTR1A was found to influence the improvement on PANSS total score, and this result remained significant after correction (p=0.0004). We did not have any other significant results of single locus in this part, however, polymorphisms on genes encoded for dopamine and serotonin receptors were found to be related with improvement on PANSS subscales in regression model.

The third part of this study is about Risperidone-induced weight-gain. Patients with more than 7% of BMI gained were defined as significant weight gain. We didn’t find any significant association with the49 single locus, but we found that BMI after treatment is influence by many polymorphisms simultaneously. These polymorphisms include HTR3A rs1062613、ABCB1 rs2032582 and HTR1A rs878567.

According to the results we found in this study, the risk for schizophrenia and response of Risperidone treatment are influenced by variations on dopamine and serotonin genes. This study set the stage for a prospective evaluation of how pharmacogenomics studies may be used to predict the risk for schizophrenia and outcome of treatment. Further studies are warranted to clarify these genetic effects.

Reference ( 451 ) 〈TOP〉

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