評估癲癇多基因風險分數在台灣族群與臨床樣本中預測及風險分層之表現

Abstract

癲癇影響全球逾五千萬人，癲癇因其病因多樣、臨床症狀複雜，導致診斷過程充滿挑戰。儘管全基因體關聯研究 (GWAS) 已識別出多個與常見癲癇相關的基因座，基於這些變異建構的多基因風險分數 (PRS) 逐漸被視為潛在的輔助診斷工具。然而，現有癲癇PRS研究主要集中於歐洲族群，其在非歐洲族群的預測效能仍缺乏驗證。 本研究評估了癲癇 PRS 在三個招募方式與表型定義各異的台灣人群資料 中之預測與分層效能。這些目標樣本分別是：台灣人體生物資料庫 (TWB) 連結全民健康保險研究資料庫 (NHIRD) 的104,680名參與者，其中依ICD診斷碼與抗癲癇藥物紀錄判定915例癲癇病例；台灣精準醫療計畫 (TPMI) 的464,596名參與者，其中依相同標準定義識別5,609例癲癇病例；以及Epi25聯盟之Epi25-TWN樣本的1,140名參與者，內含699例由臨床醫師精細診斷之癲癇個案。接著利用國際抗癲癇組織 (ILAE) 最新的GWAS數據 (族群組成：85% 歐洲、6% 亞洲、9% 非洲)，計算了所有癲癇 (All Epilepsy)、遺傳性全面性癲癇 (GGE) 及局灶性癲癇 (FE) 在這三個樣本中的PRS。隨後，透過終身風險模型、發病年齡分層分析及全表型關聯分析 (PheWAS)，全面評估其預測與風險分層能力。 研究結果顯示GGE PRS在Epi25-TWN樣本中效應最強 (每標準差OR = 1.65, R^2 = 3.2%)，與GGE具高遺傳度 (~40%) 的預期相符，但在兩個大型人口型樣本（TWB-NHIRD與TPMI）中卻僅有相對微弱的效應 (OR = 1.09¬¬–1.13 , R^2 = 0.14–0.22%)。相較之下，FE PRS在三個世代中的效應較¬為一致，但整體屬中 (OR = 1.02–¬1.16, R^2 = 0.01–0.31%）。在風險分層方面，Epi25-TWN中的效果亦最為顯著，GGE PRS排名前5% 高的個體，其患GGE風險為其餘個體的四倍以上，然而相同效應在 TWB-NHIRD 和 TPMI中則較為溫和，風險為其餘個體的不到1.5倍。此外，研究結果支持較高的PRS分數與發病年齡呈負相關，此現象在GGE中尤為顯著，進一步分析發現，將分析限制於較早發病的患者時，GGE PRS在PheWAS中呈現出與癲癇相關的特異訊號。 這項研究是目前針對非歐洲族群規模最大的癲癇 PRS 研究，發現目標樣本研究設計與表型精確度對於PRS預測力的顯著影響，並突顯未來需整合更全面的表型數據與更多元族群的癲癇GWAS，方能顯著提升PRS在跨族群的解釋力與臨床應用潛力。

Epilepsy affects over 50 million people worldwide, and its diagnosis remains challenging due to heterogeneous etiologies and diverse clinical presentations. Genome-wide association studies (GWAS) have identified dozens of loci for common epilepsies, and polygenic risk score (PRS) derived from these findings have been proposed as tools to estimate genetic susceptibility and support diagnosis. However, most epilepsy PRS studies have focused on European populations, and their performance in non-European cohorts is largely unexplored. We assessed the predictive and stratification performance of epilepsy PRSs across three Taiwanese cohorts with distinct recruitment and phenotyping strategies. These cohorts included: 104,680 individuals from the community-based Taiwan Biobank (TWB) linked to 20 years of National Health Insurance Research Database (NHIRD), with 915 epilepsy cases identified using ICD codes and antiseizure medication usage; 464,596 individuals from the multi-hospital-based Taiwan Precision Medicine Initiative (TPMI), including 5,609 cases defined using the same criteria; and 1,140 individuals (700 cases) from the Epi25-TWN cohort (Epi25 consortium) with detailed clinical phenotyping. PRSs for all epilepsy, generalized epilepsy (GGE), and focal epilepsy (FE) were derived from the most recent ILAE GWAS summary statistics (85% European, 6% Asian, 9% African). Predictive performance was evaluated using lifetime risk models, age-of-onset stratification analyses and phenome-wide association study (PheWAS). The GGE PRS showed the strongest effect in Epi25-TWN (OR = 1.65 per SD, R^2 = 3.2%) but weaker effects in the two population-based cohorts, TWB-NHIRD and TPMI (OR = 1.09–1.13, R^2 = 0.14–0.22%). In contrast, the FE PRS yielded more consistent but modest associations across cohorts (OR = 1.02–1.16, R^2 = 0.01–0.31%). Risk stratification was most effective in Epi25-TWN, where individuals in the top 5% of GGE PRS showed over fourfold higher odds of GGE. However, enrichment in the TWB-NHIRD and TPMI was modest, less than 1.5-fold. Furthermore, higher PRS was associated with an earlier age of onset across all three cohorts, especially for GGE, with epilepsy-specific signals for GGE PRS emerging in PheWAS when analyses were restricted to earlier-onset patients. This study represents the largest evaluation of epilepsy PRS performance in non-European populations to date. Our findings highlight how cohort design and phenotyping accuracy significantly influence PRS predictive utility, underscoring the critical need for richer phenotypic data and more diverse epilepsy GWAS to enhance cross-population portability and clinical applicability.