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

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。

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.