亞洲進行性核上性麻痺的遺傳分析

Abstract

研究背景：進行性核上性麻痹(Progressive supranuclear palsy, PSP)是一種進展迅速的原發性 tau蛋白病變(primary tauopathy)，臨床特徵包括帕金森氏症狀、疾病早期即姿勢不穩及頻繁跌倒、垂直方向上眼球運動障礙以及認知功能退化。PSP雖然長期以來被視為偶發性疾病，近期針對歐洲族群的全基因組關聯分析(Genome-wide association studies, GWAS)已鑑定出數個與PSP相關的風險位點(risk loci)。然而，相對於歐洲族群，亞洲族群在PSP的遺傳架構上仍有待進一步釐清。隨著針對致病機轉的療法進入早期臨床開發階段，釐清過去研究中代表性不足的族群(特別是亞洲人)的遺傳特性，對於定義特定族群的風險輪廓與致病機轉至關重要。 研究方法：本研究納入來自東亞與東南亞地區共549位PSP病患的全外顯子定序(Whole-exome sequencing, WES)數據進行分析。所有已辨識之罕見變異(次要等位基因頻率<1%)，依據ACMG準則進行致病性分類，並進行累積性罕見變異負荷量分析。針對LRRK2 G2385R及R1628P兩個亞洲族群富集之常見變異位點，我們以基因組聚合資料庫(Genome Aggregation Database, gnomAD)中的東亞與東南亞群體及臺灣人體生物資料庫(Taiwan Biobank)作為對照組，進行等位基因頻率的關聯性分析。 研究結果：在549位PSP患者中，平均發病年齡為65.06 ± 7.38歲，其中60.5%為男性，共有31位(5.65%)帶有致病性或可能致病性(pathogenic or likely pathogenic, P/LP)的變異，另外有128位(23.32%)帶有不確定意義的變異(variants of uncertain significance, VUS)。在P/LP變異攜帶者中，頻率最高的變異位於ABCA7 (25.81%)基因，其次為SMPD1 (19.35%)、BSN (9.68%)、MAPT (6.45%)，以及APP (6.45%)基因。當把P/LP與罕見VUS (次要等位基因頻率 < 1%)的攜帶者加總進行累積變異負荷分析時，頻率最高的變異為BSN基因，佔了21.59%；其次為ABCA7 (14.20%)、LRRK2 (10.80%)，和MAPT (6.82%)。透過Ingenuity Pathway Analysis (IPA)路徑分析，本研究標定出數個與PSP致病機轉相關的生物學路徑，包括：Tau蛋白穩態(tau proteostasis)、溶體(lysosomal)與脂質代謝、突觸小泡與胞內運輸(synaptic vesicular trafficking)以及粒線體功能。 結論：亞洲族群的PSP具有獨特的族群特異性遺傳架構(ancestry-specific genetic architecture)，其模式顯著不同於歐洲族群中以MAPT基因佔主導地位的遺傳特徵。本研究結果為理解亞洲PSP族群的遺傳風險提供了重要見解。

Background: Progressive supranuclear palsy (PSP) is a rapidly progressive tauopathy characterized by parkinsonism, early postural instability with frequent falls, vertical supranuclear gaze palsy, and progressive cognitive decline. Although traditionally considered a sporadic disorder, recent genome-wide association studies (GWAS) have substantially advanced the understanding of its genetic basis by identifying multiple susceptibility loci, primarily in European populations. However, the genetic architecture of PSP in Asian populations remains poorly understood. As the field moves toward mechanism-based therapeutic strategies, defining the genetic architecture of PSP in underrepresented populations, particularly Asians, is essential for identifying population-specific risk profiles and elucidating distinct pathogenic mechanisms. Methods: We analyzed whole-exome sequencing (WES) data from 549 PSP patients recruited across East and Southeast Asia. Variant frequencies were compared with two control datasets: the combined East and South Asian populations from the Genome Aggregation Database (gnomAD) and 1492 individuals from the Taiwan Biobank. Results: Among 549 PSP patients, the mean age at onset was 65.06 ± 7.38 years, and 60.5% of patients were male. Pathogenic or likely pathogenic (P/LP) variants were identified in 31 patients (5.65%), while 128 (23.32%) carried variants of uncertain significance (VUS). Among P/LP carriers, the most frequently affected genes were ABCA7 (25.81%), followed by SMPD1 (19.35%), BSN (9.68%), MAPT (6.45%), and APP (6.45%). When the cumulative burden of rare variants was evaluated, BSN emerged as the most frequently implicated gene (21.59%), followed by ABCA7 (14.20%), LRRK2 (10.80%) and MAPT (6.82%). Ingenuity Pathway Analysis identified several pathways linking to PSP, including tau proteostasis, lysosomal and lipid metabolism, synaptic vesicular and intracellular trafficking, and mitochondrial function. Conclusion: PSP in Asians has a distinct ancestry-specific genetic architecture that differs from the MAPT-dominant pattern reported in European populations. These findings provide new insights into the genetic risk of PSP in Asian populations.