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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 廖世偉 | zh_TW |
| dc.contributor.advisor | Shih-Wei Liao | en |
| dc.contributor.author | 蔡岳君 | zh_TW |
| dc.contributor.author | Yueh-Chun Tsai | en |
| dc.date.accessioned | 2025-07-02T16:22:42Z | - |
| dc.date.available | 2025-07-03 | - |
| dc.date.copyright | 2025-07-02 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-06-06 | - |
| dc.identifier.citation | [1]Peery, A. F., Crockett, S. D., Murphy, C. C., Jensen, E. T., Kim, H. P., Egberg, M. D., Lund, J. L., Moon, A. M., Pate, V., Barnes, E. L., Schlusser, C. L., Baron, T. H., Shaheen, N. J., & Sandler, R. S. (2022). Burden and Cost of Gastrointestinal, Liver, and Pancreatic Diseases in the United States: Update 2021. Gastroenterology, 162(2), 621–644. https://doi.org/10.1053/j.gastro.2021.10.017
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Human tetraspanin transmembrane 4 superfamily member 4 or intestinal and liver tetraspan membrane protein is overexpressed in hepatocellular carcinoma and accelerates tumor cell growth. Acta biochimica et biophysica Sinica, 44(3), 224–232. https://doi.org/10.1093/abbs/gmr124 [29]Diogo, D., Tian, C., Franklin, C. S., Alanne-Kinnunen, M., March, M., Spencer, C. C. A., Vangjeli, C., Weale, M. E., Mattsson, H., Kilpeläinen, E., Sleiman, P. M. A., Reilly, D. F., McElwee, J., Maranville, J. C., Chatterjee, A. K., Bhandari, A., Nguyen, K.-D. H., Estrada, K., Reeve, M.-P., … Runz, H. (2018). Phenome-wide association studies across large population cohorts support drug target validation. Nature Communications, 9(1), 4285. https://doi.org/10.1038/s41467-018-06540-3 [30]A practical guideline of genomics-driven drug discovery in the era of global biobank meta-analysis - PubMed. (n.d.). Retrieved February 8, 2025, from https://pubmed.ncbi.nlm.nih.gov/36778001/ [31]Tamber, S. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/97541 | - |
| dc.description.abstract | 膽結石是種常見消化系統疾病，復發率與衍生相關疾病造成醫療系統極大負擔。膽結石形成與膽汁酸代謝、膽固醇代謝失衡、基因背景與種族差異密切相關，但大多數膽結石疾病基因研究主採用西方人群數據庫，限制對東方人群治病性生理機轉的理解。因此，本研究利用台灣人體生物資料庫，經品質控制後共108,403名具漢族受試者進行全基因體關聯分析（GWAS），探討與膽結石相關的遺傳變異，亦進行 LDSC 分析驗證通膨程度（λGC = 1.0741；intercept = 1.0067），結果顯示通膨現象主要源自多基因性而非其他混雜因子。建構多基因風險預測模型（Polygenic Risk Score, PRS），PRS-CS 展現極高預測力（AUC = 0.98）。本研究鑑定出57個顯著基因變異位點，其中有38 個新發現，計算每個顯著基因變異位點的治病機率，以 rs80217587（TM4SF4）具有最高的後驗包含機率（PIP = 0.202），顯示其為最具潛力的致病變異位點。本研究發現的7個Lead SNP，分別對應1個控制區（RP11-626H12.1）與6個鄰近基因（TM4SF4、LRBA、UBXN2B、CYP7A1、HNF4A 和 ANO1），其中TM4SF4、LRBA、UBXN2B 和 ANO1 為首次在東亞族群提出與膽結石易染性的關聯基因。我們的研究結果指出 TM4SF4 可作為膽結石疾病早期偵測與預防性醫療管理的潛在生物標記與治療標的。。透過路徑富集分析，我們也提出三組血中生物標記群（GGT、ALT、CRP、膽酸/膽紅素前驅物等），可望作為早期非侵入性風險預測工具。搭配多基因風險分數與個人飲食改善計畫建議，有助於建立針對膽結石高風險族群之精準預防策略。 | zh_TW |
| dc.description.abstract | Gallstone disease (GSD) is a prevalent gastrointestinal disorder with high recurrence and substantial healthcare burden. Its etiology involves bile acid and cholesterol metabolism, genetic predisposition, and ethnic variation. However, most genetic studies focused on Western populations, limiting insights into East Asian-specific mechanisms. This study leveraged data from 108,403 Han Chinese individuals in the Taiwan Biobank to perform a genome-wide association study (GWAS) on GSD. After quality control and adjustment for population stratification, linkage disequilibrium score regression (LDSC) confirmed minimal inflation (λGC = 1.0741; intercept = 1.0067), suggesting that observed signals are due to polygenicity. Polygenic risk prediction using PRS-CS demonstrated strong performance (AUC = 0.98). We identified 57 significant SNPs, including 38 novel variants. Bayesian fine-mapping revealed rs80217587 (TM4SF4) as the top causal candidate (PIP = 0.202), along with 7 lead SNPs mapped to TM4SF4, LRBA, UBXN2B, CYP7A1, HNF4A, ANO1, and a non-coding region (RP11-626H12.1). TM4SF4, LRBA, UBXN2B and ANO1 are first mentioned in East Asian population. We highlight TM4SF4 as a potential biomarker and therapeutic target for the early detection and preventive management of GSD. Moreover, pathway enrichment analysis identified candidate biomarkers (GGT, ALT, CRP, bile acid precursors) for potential early, non-invasive risk laboratory test screening. By integrating PRS with personalized dietary intervention plans, we propose a precision prevention strategy tailored for individuals at high risk of GSD. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-07-02T16:22:42Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-07-02T16:22:42Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 誌謝 ii
Acknowledgements iii 摘要 iv Abstract v Contents vi List of Figures ix List of Tables x Abbreviation xi Chapter 1 Introduction 1 1.1 Research Background 1 1.2 Problem Statement 1 1.3 Research Objectives 2 1.4 Thesis Organization 2 Chapter 2 Literature Review 3 2.1 Diagnostic Criteria of Gallstone Disease 3 2.2 Genetic and Biological Mechanisms of Gallstone Formation 4 2.3 Genetic Association with Metabolic and Environmental Contexts 4 Chapter 3 Methods 5 3.1 Data Sources and Quality Control 5 3.2 Genome-Wide Association Studies (GWAS) 5 3.3 Genomic Inflation and Heritability Assessment 6 3.4 SNP-Level Statistical Analysis 7 3.4.1 Regional Association Plots 7 3.4.2 Functional Fine-Mapping 8 3.4.3 Functional Annotation Enrichment 8 3.5 Polygenic Risk Score (PRS) 9 3.6 SNP-to-Phenotype Association Analysis 10 3.6.1 Phenome-Wide Association Study (PheWAS) 10 3.6.2 GWAS Catalog 11 3.7 Gene-Level Interpretation 11 3.7.1 Protein-protein Interaction Network 11 3.7.2 Pathway Enrichment Analysis 11 3.8 Data Availability 12 Chapter 4 Results 13 4.1 Study Pipeline of The Genome-to-Phenome Approach 13 4.2 Genome-Wide Association Studies (GWAS) 14 4.3 Quality Control Analysis 17 4.4 SNP-Level Statistical Analysis 17 4.5 Polygenic Risk Score (PRS) 22 4.6 SNP-to-Phenotype Association 23 4.7 Gene Level Interpretation 25 Chapter 5 Discussion 28 5.1 Novel Findings 28 5.2 Clinical Significance and Intervention Strategy 28 5.3 Study Limitation 29 5.4 Future Study Suggestion 30 5.5 Conclusion 31 Chapter 6 Ethics Statement 32 6.1 Competing Interests and Ethic Approval and Patient Consent 32 6.2 Contribution 32 Bibliography 33 Appendix 40 Supplemental Table 1. Cohort characteristics of Taiwan Biobank participants 40 Supplemental Table 2A. GWAS Catalog for SNPs annotated by HNF4A 41 Supplementary Table 2B. GWAS Catalog for SNPs annotated by UBXN2B/CYP7A 61 Supplementary Table 2C. GWAS Catalog for SNPs annotated by TM4SF4 63 Supplementary Table 2D: GWAS Catalog for SNPs annotated by LRBA 65 Supplementary Table 2E. GWAS Catalog for SNPs annotated by ANO1 67 Supplementary Table 3. Summary statistic of protein-to-protein enrichment 68 Supplementary figure 1. Receiver operating characteristic (ROC) curves comparing predicting GSD PRS models with and without cofounders 72 Supplementary figure 2. PheWAS disease model interpretation 73 Supplementary figure 3. Receiver operating characteristic (ROC) curves for different subgroups. 74 List of Figures Page Figure 1. A flowchart of a Genome-to-Phenome approach with PRS model in our study. 13 Figure 2. Manhattan plot for gallstone disease association results. 14 Figure 3. Evaluation on statistical calibration and polygenic contribution. 14 Figure 4A. Regional association plot for rs2131242 on chromosome 11. 18 Figure 4B. Regional association plot for rs902870 on chromosome 11. 18 Figure 4C. Regional association plot for rs66779552 on chromosome 3. 18 Figure 4D. Regional association plot for rs1580180 on chromosome 8. 19 Figure 4E. Regional association plot for rs17503902 on chromosome 4. 19 Figure 4F. Regional association plot for rs7005978 on chromosome 8. 19 Figure 4G. Regional association plot for rs1800961 on chromosome 20. 20 Figure 5. Fine-mapping results of posterior inclusion probability (PIP) for SNP identifiers in credible sets across chromosomes and functional annotation enrichment. 21 Figure 6. Receiver operating characteristic (ROC) curves comparing predicting GSD PRS models with and without confounder adjustment. 23 Figure 7. Phenome-Wide association study (PheWAS) disease model interpretation. 23 Figure 8. The protein-to-protein network diagram. 26 List of Tables Table 1. GWAS summary statistics of 57 Significant SNPs and fine mapping of posterior inclusion probabilities (PIPs) with 95% credible sets 15 Table 2. Comparison of the predictive performance of different PRS models 22 Table 3. 12 Reported SNPs in GWAS catalog and its most significant trait 24 Table 4. Pathway enrichment analysis 27 | - |
| dc.language.iso | en | - |
| dc.subject | 膽結石 | zh_TW |
| dc.subject | 全基因組關聯研究 | zh_TW |
| dc.subject | 表型全關聯研究 | zh_TW |
| dc.subject | 台灣人體生物資料庫 | zh_TW |
| dc.subject | 多基因風險評分 | zh_TW |
| dc.subject | 蛋白質-蛋白質交互作用 | zh_TW |
| dc.subject | 血液檢測 | zh_TW |
| dc.subject | 預防醫學 | zh_TW |
| dc.subject | prevention medicine | en |
| dc.subject | Gallstone | en |
| dc.subject | GWAS | en |
| dc.subject | phenome-wide association study | en |
| dc.subject | Taiwan Biobank | en |
| dc.subject | polygenic risk score | en |
| dc.subject | Protein-protein interaction network | en |
| dc.subject | laboratory test | en |
| dc.title | 台灣族群膽結石疾病遺傳易感性研究： 基因-表型組學方法與多基因風險評分模型 | zh_TW |
| dc.title | Genetic Susceptibility of Gallstone Disease in Taiwanese Population: A Genome-Phenome Approach with Polygenic Risk Score | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.coadvisor | 李建璋 | zh_TW |
| dc.contributor.coadvisor | Chien-Chang Lee | en |
| dc.contributor.oralexamcommittee | 郭育良;李逸元 | zh_TW |
| dc.contributor.oralexamcommittee | Yue-Liang Guo;Yi-Yuan Lee | en |
| dc.subject.keyword | 膽結石,全基因組關聯研究,表型全關聯研究,台灣人體生物資料庫,多基因風險評分,蛋白質-蛋白質交互作用,血液檢測,預防醫學, | zh_TW |
| dc.subject.keyword | Gallstone,GWAS,phenome-wide association study,Taiwan Biobank,polygenic risk score,Protein-protein interaction network,laboratory test,prevention medicine, | en |
| dc.relation.page | 74 | - |
| dc.identifier.doi | 10.6342/NTU202500806 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2025-06-06 | - |
| dc.contributor.author-college | 共同教育中心 | - |
| dc.contributor.author-dept | 智慧醫療與健康資訊碩士學位學程 | - |
| dc.date.embargo-lift | 2025-07-03 | - |
| 顯示於系所單位： | 智慧醫療與健康資訊碩士學位學程 | |
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