臺灣博碩士論文加值系統

雙極性情緒障礙（Bipolar affective disorder；又稱躁鬱症）是一種常見的複雜型多基因遺傳疾病，患者具有狂躁與憂鬱兩者相互循環的情緒周期。先前的研究顯示血清素(一種大腦皮質上主要的神經傳導物質，已知對情緒的調控有影響)，可能與躁鬱症的病理成因有關。本研究之目的即為瞭解：是否這些血清素系統基因上的序列變異，會影響其表現蛋白之正常功能，導致血清素傳導系統的缺失，甚而進一步的引發躁鬱症。我們利用遺傳和功能性的分析，研究了數個參與在血清素系統中的基因，包括第二血清素合成酵素(neuronal tryptophan hydroxylase; TPH2)、血清素受體(serotonin receptors; HTRs)以及其代謝酵素(monoamine oxidase A; MAOA)。這些研究結果以及之前本實驗室針對第一血清素合成酵素(tryptophan hydroxylase; TPH1)和血清素轉運子(serotonin transporter; SLC6A4)所做的關連性分析皆指出血清素系統基因上的多型性標誌分佈，與躁鬱症之間皆有強弱不等的相關性存在。針對這些序列變異所做的功能性分析，也證實這些變異的確會造成蛋白質功能或表現量上的異常。另一方面，存在於多個序列變異點，或數個基因之間的相互作用，也都在本研究中被發現；並帶出各不相同的致病機轉。這些結果符合了之前對於此種複雜性常見疾病所提出的“常見疾病-常見變異”的假說，也就是這些常見疾病的發生，其實與許多廣泛分佈於族群中的變異有關。在這個假說之下，每一個變異點或基因對於疾病的貢獻也許並不大，對於疾病的發生也非必要因素。然而，多個遺傳因子彼此交互作用的綜合影響，卻會導致像躁鬱症此種常見的複雜性疾病發生。這些發現證實了血清素系統在躁鬱症的致病機轉上的確扮演非常重要的角色，並期待此研究能對躁鬱症的致病機轉和其治療有所貢獻。

Bipolar affective disorder (BPD) characterized by manic and depressive episodes is a common and complex disease. Serotonin (5-hydroxytryptamine; 5-HT) is a key neurotransmitter in the central nervous system (CNS), and dysfunction of serotonin transmission in the CNS has been implicated in several psychiatric diseases including BPD. This study aimed to examine whether sequence variants of serotonergic genes, that impair proteins’ function and contribute to the dysfunction of serotonin transmission, lead to the development of BPD. The genetic and functional effects of serotonergic genes, including serotonin receptors (HTRs), neuronal tryptophan hydroxylase (TPH2), and monoamine oxidase A (MAOA), were demonstrated. Results from these studies combined with previous reports of tryptophan hydroxylase 1 (TPH1) and serotonin transporter (SLC6A4), which were done in our laboratory using the same dataset, successfully identified weak-to-strong associations between polymorphisms of these genes with BPD in single-locus or haplotype levels. Further functional analyses using reporter gene and enzyme-activity assays indicated that the alteration of sequence variants indeed affected the protein function. Finally the higher order interactions between polymorphisms of the TPH2 gene and between TPH2 and TPH1 have been demonstrated. Both the intra- and inter-gene interactions among variants of serotonin system were found and showed contribution to BPD etiology. Results from these studies support the hypothesis that the alteration in each single variant or serotonergic gene only contribute to partial effect. However, the synergic effect of interactions between variants and genes in the same pathway that co-contribute to influence serotonin neurotransmission is important in BPD etiology.

摘　　要…………………………………………………………………...i
Abstract　………………………………………………………………………..ii
誌　　謝………………………………………………………………….iii
Table　of　Contents　……………………………………………………………..v
List of Tables …………………………………………………………………viii
List of Figures ………………………………………………………………….ix

CHAPTER ONE ……………………………………………………………..1
Literature Review ……………………………………………………………..1
1.1 Bipolar affective disorder (BPD) ………………………………………..2
1.1.1 Epidemiological studies of BPD ………………………………………..2
1.1.2 Molecular genetic studies of BPD ………………………………………..2
1.1.2.1 Linkage analysis ………………………………………………………..3
1.1.2.2 Association analysis …………………………………………………..3
1.2 Serotonergic transmission system ………………………………………..4
1.3 Serotonergic system genes and BPD …………………………………..7
1.3.1 Tryptophan hydroxylase 1 (TPH1) …………………………………..8
1.3.2 Neuronal tryptophan hydroxylase (TPH2) ……………………………..8
1.3.3 Serotonin receptors (HTRs) ……………………………………………..9
1.3.4 Serotonin transporter (SLC6A4) ………………………………………..9
1.3.5 Monoamine Oxidase A (MAOA) ………………………………………10
1.4 Genetic heterogeneity of complex disease ……………………………11
1.5 Hypothesis and research objective ………………………………………12

CHAPTER TWO ……………………………………………………………14
Receptor mediated effect of serotonergic transmission in patients
with bipolar affective disorder ……………………………………………14
2.1 Abstract ………………………………………………………………...15
2.2 Introduction ……………………………………………………………15
2.3 Materials and Methods …………………………………………………17
2.3.1 Sample collection and DNA preparation ……………………………17
2.3.2 Selection of candidate genes and markers ……………………………18
2.3.3 Genotyping procedures and primer design ……………………………18
2.3.4 PCR reaction ……………………………………………………………19
2.3.5 Genotype analysis ………………………………………………………19
2.3.6 Statistical methods ………………………………………………………19
2.4 Results …………………………………………………………………22
2.5 Discussion …………………………………………………………………23

CHAPTER THREE ………………………………………………………29
Functional polymorphisms of the human tryptophan hydroxylase
2 genes confer risk for bipolar disorder in Han Chinese …………………29
3.1 Abstract …………………………………………………………………30
3.2 Introducton ……………………………………………………………30
3.3 Material and methods …………………………………………………32
3.3.1 Subjects …………………………………………………………………32
3.3.2 Polymorphism screening ……………………………………………32
3.3.3 Marker selection and genotyping assays ……………………………33
3.3.4 Quantification of brain tryptophan hydroxylase ………………………33
3.3.4.1 Cell culture and human brain cDNA panel ……………………………33
3.3.4.2 RNA isolation and quantitative real-time RT-PCR …………………33
3.3.5 Functional assay of TPH2 5’-promoter polymorphisms ……………34
3.3.6 Functional assay of TPH2 exon2 C2755A polymorphism ……………34
3.3.7 Statistical analysis ………………………………………………………34
3.4 Results …………………………………………………………………34
3.4.1 Identification of TPH2 sequence variants ……………………………34
3.4.2 Single-locus association analysis ………………………………………34
3.4.3 Linkage disequilibrium (LD) mapping …………………………………35
3.4.4 Haplotype association analysis ………………………………………39
3.4.5 Promoter activity in T-703G and T-473A reporter constructs ………41
3.4.6 Determination of POU3F2 binding by electrophoretic
mobility shift assay (EMSA) …………………………………………………41
3.4.7 TPH enzyme activity in C2755 versus A2755 constructs ……………42
3.4.8 The interaction between TPH2 and TPH1 …………………………..42
3.4.8.1 Expression of mRNAs for TPH-1 and -2 in the Human Brain ………42
3.4.8.2 Combined Genotyping Analysis of TPH1 and TPH2 …………………43
3.5 Discussion …………………………………………………………………49

CHAPTER FOUR ……………………………………………………………55
Haplotype association of Monoamine Oxidase A Gene and
Bipolar Affective Disorder in Han Chinese men………………………………55
4.1 Abstract …………………………………………………………………56
4.2 Introduction ……………………………………………………………56
4.3 Materials and methods …………………………………………………58
4.3.1 Sample collection and DNA preparation ……………………………58
4.3.2 Polymorphism Genotyping ……………………………………………59
4.3.3 Statistical Analysis ………………………………………………………60
4.4 Results …………………………………………………………………60
4.4.1 Polymorphism Genotyping and Single-locus Association Analysis …60
4.4.2 Linkage Disequilibrium Measurement and Haplotype Analysis ………61
4.5 Discussion …………………………………………………………………61

CHAPTER FIVE …………………………………………………………….66
General Discussion and Conclusion ……………………………………….66
5.1. General Summary ……………………………………………………….67
5.1.1 Epistatic interaction effects on BPD etiology ……………………….67
5.1.1.1 Interaction among polymorphisms of single gene ………………….67
5.1.1.2 Interaction among multiple causing gene of serotonin system ……….68
5.1.2 Interaction model of other complex disease etiology ………………….68
5.1.3 Common variants in pathogenesis of complex common disease ……….69
5.1.4 Interaction-considered approaches ……………………………………….69
5.1.5 Conclusion and Significance of this study …………………………….70

References …………………………………………………………………..71
Appendix Methods ……………………………………………………………..83
Appendix Tables ……………………………………………………………. 91
Appendix Figures …………………………………………………………….108

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