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研究生:林莉庭
研究生(外文):Lin, Li-Ting
論文名稱:單胺氧化酶 A 基因多態性的功能性神經影像統合分析
論文名稱(外文):Functional Neuroimaging Meta-analysis of Monoamine oxidase A with a variable number tandem repeat (MAOA-VNTR) polymorphism
指導教授:鄭雅薇鄭雅薇引用關係
指導教授(外文):Cheng, Ya-Wei
口試委員:陳澂毅范揚騰陳毓君
口試委員(外文):Chen, Cheng-YiFann, Yang-TerngChen, Yu-Chun
口試日期:2021-12-16
學位類別:碩士
校院名稱:國立陽明交通大學
系所名稱:神經科學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2021
畢業學年度:110
語文別:英文
論文頁數:82
中文關鍵詞:單胺氧化酶 A 基因高基因及低基因表現型統合分析-大腦強的活化反應高階認知功能的差異負向情緒及社會痛苦處理的差異
外文關鍵詞:Monoamine oxidase A (MAOA)- VNTR genotypegenotypes: H and L expressioncoordinate meta-analysishigh order cognitive functionnegative emotionsocial pain processing
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單胺氧化酶 A 基因(Monoamine oxidase A gene) 被認為會影響生理機能及行為表現。為了解 MAOA 基因對於人類的潛在影響,過去已有學者透過非侵入式的儀器(像是腦電波、腦造影等方式)來了解基因對於人類大腦活動的變化。此篇研究將透過功能性腦造影(fMRI, PET, EEG neuroimaging 等)統合分析-coordinate meta-analysis(整合過去功能性腦造影活化結果)的方式釐清 MAOA 基因多態性(MAOA variable number tandem repeat/
MAOA-VNTR 兩個基因型的大腦強活化反應及比較基因型的強活化反應(相似、相異處)來推測不同 MAOA 基因表現型(MAOA variable number tandem repeat/ MAOA-VNTR; 可變數目串聯重複多態性:可分為兩種基因表現型- 高和低)對於行為的可能影響。

在執行統合分析前,選擇預納入分析的文獻是一個很重要且須嚴謹的流程(依據 Prisma guideline 的指示)。文獻的來源有以下三個主要的資料庫,包含 Pubmed, Medline online (Ovid)和 Web of Science (WoS),另外部分文獻來源為預納入文獻的依據(reference), google scholar 的中文資料庫以及 google 搜尋引擎,而搜尋的方式為輸入一致的關鍵字: (MAOA OR "Monoamine oxidase A" OR "warrior gene" OR "MAOA-VNTR"
OR "MAOA genotype") AND (fMRI OR "functional magnetic resonance imaging" OR PET OR "Positron emission tomography" OR neuroimaging)。最後總共得到 17 篇(10 篇/10 個實驗為高基因表現型;10 篇/12 個實驗為低基因表現型)納入統合分析。在分析後Jackknife Sensitivity analysis 檢測研究結果是否具有可重複性、I2 value 去了解所納入之文章是否具有異質性(Heterogeneity)及使用具客觀性特質的Egger’s test 去了解納入之文獻是否有出版偏誤(Publication bias)。此外,也使用了查看腦造影影像的軟體- MRIcron 中的「重疊」功能,去了解兩者基因型強活化的相似、差異之處。

研究結果顯示,兩個基因型背後的大腦活化反應較強的神經網絡和過去研究認為一致,高基因型的人確實在抑制控制、注意力控制、工作記憶相關的腦區有較高的活化量,低基因型的人也在臉部情緒處理相關腦區有較高的活化量。另外,根據兩個基因型各自較高活化量的腦區及過去研究的討論,我們推測了基因-大腦-行為之間的可能關聯性。本篇研究認為高基因型的人受到高階認知功能(額葉、頂葉)的影響使得他們相對不容易有暴力行為、特質;低基因表現型的人則可能受到負向情緒、社會痛苦處理(額葉、顳葉及皮質下腦區)的影響使他們較容易有暴力行為、特質。
Background
The gene, Monoamine oxidase A gene (MAOA gene) was considered to play an important role in physiology and behavior. Some scholars have used non-invasive tools, e. g. brain waves, neuroimaging and others to investigate how gene affects on neural activities. The aim of this study is to clarify the stronger activated responses in each genotype of Monoamine
oxidase A gene variable number tandem repeat (MAOA-VNTR) with coordinate meta-analysis—the way to integrate previous results of papers associated with MAOA-VNTR, functional neuroimaging and compare stronger activated responses of two genotypes (H, L expression allele) to figure out the potential influence of MAOA-VNTR genotypes on behavior.

Method and Materials
In this study, a system literature and meta-analysis was done by following Prisma guidelines to clarify the activated responses of two genotypes in MAOA-VNTR. The literature selection was based on three main databases: Pubmed, Medline online (Ovid) and Web of science (WoS) and other resources, e.g. reference from included paper, Chinese database of google scholar, thesis from google search with keyword: (MAOA OR "Monoamine oxidase A" OR "warrior gene" OR "MAOA-VNTR" OR "MAOA genotype") AND (fMRI OR "functional magnetic resonance imaging" OR PET OR "Positron emission tomography" OR neuroimaging), 17 papers were found (10 papers/10 experiments for stronger responses in people with H expression and 10 papers/12 experiments for stronger responses in MAOA-L carriers). And the results of meta-analysis were validated with Jackknife sensitivity analysis, measurement of heterogeneity- I2 value and measurement of publication bias—Egger’s test (Objective). Additionally, to see the similarities and differences of stronger activated responses of two genotypes, we overlapped them with an imaging viewer-- MRIcron.

Results and Conclusion
H carriers indeed activated more on neural circuits associated with inhibitory control, working memory and attention control and L carriers showed stronger activation on neural circuit regarding facial emotion processing as ideas of previous studies. Additionally, based on the individually greater responses of each genotype and previous studies, the gene-brain-behavior potential relationship is inferred. H carriers were suggested to have less tendency to aggressive behavior modulated by high order cognitive function with brain regions: frontal and parietal lobe. As for L carriers, they were proposed to have higher risk for aggressive behavior modulated by social pain and negative emotion processing with brain regions: frontal, temporal lobe and subcortical regions.
中文摘要 i
ABSTRACT ii
Contents iii
LIST OF FIGURES v
LIST OF TABLES vi

CHAPTER 1—INTRODUCTION 1
1. 1 Background 2
1. 2 Definition of Monoamine oxidase A (MAOA) and it’s polymorphism 2
1. 3 Previous studies related to MAOA 3
1. 4 The aim and hypothesis of study 10

CHAPTER 2—METHODS and Materials 12
2. 1 Literature selection and criteria setting 13
2. 1. 1 Information sources and search strategy 13
2. 1. 2 Eligibility criteria 14
2. 1.3 Quality of included papers- assessment risk of bias (RoB) 16
2. 2 Voxel- based meta-analysis with ES-SDM 20
2. 3 Validation analysis 22
2. 3. 1 Jackknife sensitivity analysis 22
2. 3. 2 Heterogeneity between included studies - I2 value 23
2. 3. 3 The publication bias for included papers– Egger’s test 24
2. 4 The comparison of two genotypes (H, L expression) 24

CHAPTER 3—RESULTS 25
3. 1 literature selection and criteria setting 25
3. 2 Validation analysis 32
3. 2. 1 Jackknife sensitivity analysis 32
3. 2. 2 Heterogeneity between included studies - I2 value 33
3. 2. 3 Publication bias—Egger’s test 34
3. 2. 4 Summary for validation analysis 35
3. 3 The results from coordinate meta-analysis with ES-SDM 35
3. 4 The comparison of two genotypes (H, L expression) 39

CHAPTER 4—DISCUSSION 40
4. 1 H carriers 41
4. 1. 1 Alteration of neural network related to H carriers 41
4. 1. 2 Gene-brain-behavior potential relationship in H carriers 45
4. 1. 3 Summary 50
4. 2 L carriers 50
4. 2. 1 Alteration of neural network related to L carriers 50
4. 2. 2 Gene-brain-behavior potential relationship in L carriers 52
4. 2. 3 Summary 58
4. 3 Limitation 59 4. 3. 1 The results of analysis cannot be applicable to all sample, condition 59
4. 3. 2 Limited information of the influence from MAOA gene on behavior 59
4. 4 Conclusion 60
CHAPTER 5—Reference 62
TABLES 75
Appendix 80


LIST OF FIGURES
Figure 1. The potential modal for the interaction of MAOA gene and behavior 4
Figure 2. A causal-model diagram of a potential gene-brain-cognition-behavior pathway —MAOA-L to reactive aggression 9
Figure 3. The schematic diagram for Jackknife sensitivity analysis 23
Figure 4. Literature selection with criteria setting 29
Figure 5. Quality of included papers (Risk of Bias) 30
Figure 6. The activated responses of stronger activation in H expression 37
Figure 7. The activated responses of stronger activation in L expression 38
Figure 8. The comparison between two genotypes 39

LIST OF TABLES
Table 1. The genotypes of MAOA-VNTR 3
Table 2. The JBI Critical Appraisal Checklist for analytical cross-sectional studies, 2020……….18
Table 3. The color meaning in contrast of neuroimaging results . 24
Table 4. Quality of included cross-sectional studies (Risk of Bias) 31
Table 5. Results of Jackknife sensitivity analysis and I2 value in the condition of stronger activation in H expression 76
Table 6. Results of Jackknife sensitivity analysis and I2 value in the condition of stronger activation in L expression 77
Table 7. The activated responses of stronger activation in H expression 36
Table 8. The activated responses of stronger activation in L expression 38
Table 9. Studies included in meta-analysis 78
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