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標題: | 精神分裂症的失匹配負波異常和NMDA受體基因的相關性研究 Genetic Association Study of Mismatch Negativity and NMDA Receptor Genes in Schizophrenia |
作者: | Yi-Ting Lin 林奕廷 |
指導教授: | 胡海國 |
關鍵字: | 失匹配負波,精神分裂症,麩胺酸,NMDA受體,關聯分析,單核苷,酸多型性, mismatch negativity,schizophrenia,glutamate,NMDA receptor,association analysis,single nucleotide polymorphism, |
出版年 : | 2011 |
學位: | 碩士 |
摘要: | 背景
失匹配負波(Mismatch negativity,簡稱MMN)是一種聽覺事件誘發電位,和N-methyl-D-aspartic acid (NMDA)受體功能有關,NMDA受體功能異常是精神分裂症核心的病理現象。MMN缺損被證實是慢性精神分裂症顯著的神精生理學現象,其效果大小約為0.99。MMN也是精神分裂症可能的內表現型之一,有助於複雜遺傳疾病的關聯性研究。所以本研究有兩個假說: (1) NMDA受體次單元基因和精神分裂症有關聯; (2) NMDA受體次單元基因和MMN有關聯。 研究方法 本研究為病例對照單核苷酸多型性(single nucleotide polymorphism,簡稱SNP)關聯性研究,研究個案包括138位精神分裂症患者和103位健康受試者。分析的NMDA受體次單元基因包括GRIN1、GRIN2B、GRIN2C、GRIN2D和GRIN3B,另外也探討GRID1這個基因。使用的遺傳標致為haplotype-tagged SNP以及經文獻報告和精神分裂症有顯著關聯的SNP。SNP以MassArray iPLEX SNP genotyping的方式定序;關聯分析以單一SNP及單套體(haplotype-based)為單位。驗證第二個假說時,將先檢查基因型和生病狀態的交互作用對於MMN有無影響。如果交互作用顯著,再分別於個案組和對照組分析MMN和SNP的關聯。對於名義p值小於0.05的結果,用permutation 一萬次的方式得到經驗p值,以減少多重比較的影響。本研究也分析SNP-SNP交互作用對於罹病狀態和MMN的影響。 結果 精神分裂症患者有顯著的MMN 缺損。在48個被定序的SNP中,有40個通過品質檢查標準。這40個SNP和精神分裂症沒有顯著關聯;但是在健康受試者,位於GRIN3B的rs2240158在additive model和dominant model都和MMN有顯著關聯,經驗p值分別為0.039和0.013。單套體分析和SNP-SNP交互作用分析沒有顯著發現。 結論 我們的資料不支持GRIN1、GRIN2B、GRIN2C、GRIN2D、GRIN3B和GRID1為精神分裂症致病基因的假說。在健康受試者GRIN3B的rs2240158與MMN有顯著關聯。GRIN3B的功能以及其和MMN的關聯,需要更多研究去探討證實。 Background Mismatch negativity (MMN) is an auditory event-related potential and is related to the N-methyl-D-aspartic acid (NMDA) receptor function. The NMDA receptor system dysfunction is a core pathology of schizophrenia. MMN deficit is a robust neurophysiological feature in chronic schizophrenia, with effect size around 0.99. It is also a candidate endophenotype for schizophrenia and may be useful for the association analysis of this complex genetic disorder. In this study, we hypothesized that (1) NMDA receptor subunits genes are associated with schizophrenia, and (2) NMDA receptor subunits genes are associated with MMN. Method The study is a case-control single nucleotide polymorphism (SNP) association analysis. 138 schizophrenia patients and 103 healthy controls were enrolled. NMDA receptor subunit genes were GRIN1, GRIN2B, GRIN2C, GRIN2D, and GRIN3B and GRID1 were investigated. Haplotype-tagged SNPs and SNPs reported to be significantly associated with schizophrenia were genotyped by MassArray iPLEX SNP genotyping system. Both single-SNP-based and haplotype-based association analyses were conducted. To test the second hypothesis, interaction between SNP and disease status was explored first. If the interaction term was significant, separate analysis would be done in case group and control group respectively. Each nominally significant result was permuted for 10,000 times to get empirical p-value, in order to decrease the influence of multiple comparison. The epistatic effects on affected status and MMN were analyzed as well. Results MMN was significantly impaired in schizophrenia patients. 48 SNPs were genotyped, and 40 of them passed the quality control criteria. None of the 40 SNPs were associated with affected status. In healthy subject group, rs2240158 of GRIN3B was significantly associated with MMN in both additive model (empirical p-value 0.039) and dominant model (empirical p-value 0.013). Haplotype-based and epistatical association analysis yielded no significant result. Conclusions Our data didn’t support GRIN1, GRIN2B, GRIN2C, GRIN2D, GRIN3B, and GRID1 as candidate genes for schizophrenia. Rs2240158 of GRIN3B was significantly associated with MMN in healthy subjects. The functional significance and the association with MMN need further studies. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/47142 |
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顯示於系所單位: | 臨床醫學研究所 |
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