Rare-Variant Burden across Lysosomal Genes Implicates Sialylation and Ganglioside Metabolism in Parkinson's Disease

IF 7.7 1区医学 Q1 CLINICAL NEUROLOGY

Movement Disorders Pub Date : 2026-09-24 Epub Date: 2026-06-10 DOI:10.1002/mds.70391

Konstantin Senkevich MD, PhD, Sitki Cem Parlar BSc, Cloe Chantereault, Lang Liu MBI, Eric Yu PhD, Uladzislau Rudakou MD, MSc, Jamil Ahmad PhD, Jennifer A. Ruskey MD, Farnaz Asayesh MSc, Dan Spiegelman MSc, Cheryl Waters MD, Oury Monchi PhD, Yves Dauvilliers MD, PhD, Nicolas Dupré MD, FRCP, Lior Greenbaum MD, PhD, Sharon Hassin-Baer MD, Irina Miliukhina MD, PhD, Alla Timofeeva MD, PhD, Anton Emelyanov PhD, Sofya Pchelina DrSci, Roy N. Alcalay MD, MSc, Ziv Gan-Or MD, PhD

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引用次数: 0

Abstract

Background

Lysosomal dysfunction is central to Parkinson's disease (PD) pathogenesis, with GBA1 representing the strongest established genetic risk factor. Numerous other genes involved in lysosomal sphingolipid, glycosphingolipid, and ceramide metabolism have been proposed as contributors to PD, highlighting the need for genetic analyses across these pathways.

Objectives

The aim was to evaluate the contribution of rare variants across lysosomal genes to PD risk.

Methods

We analyzed rare variants (minor allele frequency ≤0.01) across 36 lysosomal genes in 8267 individuals with PD and 68,208 controls, including 793 early-onset PD (≤50 years) cases. Targeted sequencing was performed in four cohorts at McGill University (3456 cases and 2664 controls) and combined with whole-genome sequencing data from the United Kingdom (UK) Biobank (2848 cases, 62,451 controls) and the Accelerating Medicines Partnership-PD cohort (1963 cases, 3093 controls). Associations were tested using Sequence Kernel Association Test-Optimal across variant classes (rare variants, nonsynonymous, loss-of-function, and predicted damaging variants with combined annotation-dependent depletion score >20), followed by meta-analysis across cohorts. Domain-level analyses were performed for variants located within protein domains. False discovery rate (FDR) correction was applied.

Results

Meta-analysis identified a significant association between rare variants in ST3GAL3 and Parkinson's disease (Pfdr = 0.04). Domain-based analyses showed enrichment of nonsynonymous variants within the β-acetyl-hexosaminidase–like domain of HEXA (P = 8.0 × 10⁻⁴), although this signal did not survive correction (Pfdr = 0.154). In early-onset PD, domain-based analyses identified significant associations in NAGLU (Pfdr = 7.3 × 10⁻⁶) and ST3GAL5 (Pfdr = 0.03).

Conclusions

Rare variants across multiple lysosomal pathways, particularly those related to sialylation, ganglioside metabolism, ceramide biology, and lysosomal proteolysis, may contribute to PD susceptibility beyond GBA1, highlighting pathways for future replication and investigation. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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溶酶体基因的罕见变异负担与帕金森病的唾液化和神经节苷代谢有关。

背景：溶酶体功能障碍是帕金森病（PD）发病机制的核心，其中GBA1代表了最强的已知遗传危险因素。许多参与溶酶体鞘脂、鞘糖脂和神经酰胺代谢的其他基因被认为是PD的因素，强调了对这些途径进行遗传分析的必要性。目的：目的是评估跨溶酶体基因的罕见变异对帕金森病风险的贡献。方法：我们分析了8267例PD患者和68208例对照组的36个溶酶体基因的罕见变异（次要等位基因频率≤0.01），其中包括793例早发性PD（≤50年）病例。在麦吉尔大学（McGill University）的四个队列中（3456例和2664例对照）进行了靶向测序，并结合了英国生物银行（UK）的全基因组测序数据（2848例，62451例对照）和加速药物合作伙伴- pd队列（1963例，3093例对照）。使用序列核关联测试-最优（Sequence Kernel Association Test-Optimal）跨变异类（罕见变异、非同义、功能丧失和预测的破坏性变异，结合注释依赖耗尽评分bbb20）进行关联测试，然后进行跨队列的荟萃分析。对位于蛋白质结构域内的变异进行结构域水平分析。应用错误发现率（FDR）校正。结果：荟萃分析发现ST3GAL3罕见变异与帕金森病之间存在显著关联（Pfdr = 0.04）。基于结构域的分析显示，在HEXA的β-乙酰基-己糖氨基酶样结构域内富集了非同义变体（P = 8.0 × 10-4），尽管该信号没有经过校正（Pfdr = 0.154）。在早发性PD中，基于结构域的分析发现了NAGLU （Pfdr = 7.3 × 10-6）和ST3GAL5 （Pfdr = 0.03）的显著相关性。结论：在多种溶酶体途径中，特别是与唾液化、神经节苷脂代谢、神经酰胺生物学和溶酶体蛋白水解相关的罕见变异，可能导致GBA1以外的PD易感性，这是未来复制和研究的重要途径。©2026作者。Wiley期刊有限责任公司代表国际帕金森和运动障碍学会出版的《运动障碍》。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Movement Disorders 医学-临床神经学

CiteScore

13.30

自引率

8.10%

发文量

371

审稿时长

12 months

期刊介绍： Movement Disorders publishes a variety of content types including Reviews, Viewpoints, Full Length Articles, Historical Reports, Brief Reports, and Letters. The journal considers original manuscripts on topics related to the diagnosis, therapeutics, pharmacology, biochemistry, physiology, etiology, genetics, and epidemiology of movement disorders. Appropriate topics include Parkinsonism, Chorea, Tremors, Dystonia, Myoclonus, Tics, Tardive Dyskinesia, Spasticity, and Ataxia.