X染色体的基因分析将基因座与帕金森病的进展相关联。

Genetic Analysis of the X Chromosome Associates Loci with Progression of Parkinson's Disease.

作者信息

Liao Yu, Wu Hao, Wang Junhao, Corvol Jean-Christophe, Maple-Grødem Jodi, Campbell Meghan C, Elbaz Alexis, Brice Alexis, Schwarzschild Michael A, Taba Pille, Kõks Sulev, Beach Thomas G, Alves Guido, Tysnes Ole-Bjørn, Perlmutter Joel S, Maiti Baijayanta, van Hilten Jacobus J, Barker Roger A, Williams-Gray Caroline H, Scherzer Clemens R, Liu Ganqiang

机构信息

Shenzhen Key Laboratory of Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China.

Department of Medical Informatics and Neurobiology Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, Guangdong, China.

出版信息

Mov Disord. 2025 Jun 3. doi: 10.1002/mds.30252.

DOI:10.1002/mds.30252

PMID:40459076

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12353966/

Abstract

BACKGROUND

Genetic variants on the X chromosome have been linked to susceptibility for Parkinson's disease (PD), but their roles in disease progression remain unclear.

OBJECTIVES

This study investigated associations between X chromosome variants and longitudinal cognitive decline or motor impairment in patients with PD.

METHODS

We conducted combined (male + female) and stratified X-chromosome-wide survival studies (XWSS) in 4467 patients with PD with 33,406 longitudinal visits. Cognitive decline was defined as global cognitive impairment (GCI, Mini Mental State Exam score ≤25), whereas motor impairment was evaluated by Hoehn and Yahr stage 3 (HY3). Expression quantitative trait locus (eQTL) and genetic colocalization analyses were systematically performed.

RESULTS

We identified 40 common variants in the X-chromosome-wide screen associated with longitudinal progression of PD with P-value <9.27 × 10, including 11 independent loci associated with cognitive decline and two with motor impairment. The rs142724191 and rs144112368 variants were associated with cognitive decline in both combined and male-only analyses. rs111708875 reached genome-wide significance for motor progression in female cases (hazard ratio [HR] = 3.98, 95% confidence interval [CI]: 2.54-6.25) with P-value = 1.84 × 10. All these variants were independent with X chromosome susceptibility loci associated with PD, Alzheimer's disease, or Lewy body dementia.

CONCLUSIONS

Our XWSS identified novel genetic progression-associated loci on the X chromosome for PD, providing new insights into the X chromosome-linked genetic underpinnings of PD. © 2025 International Parkinson and Movement Disorder Society.

摘要

背景

X染色体上的基因变异与帕金森病（PD）的易感性有关，但其在疾病进展中的作用仍不清楚。

目的

本研究调查了PD患者X染色体变异与纵向认知衰退或运动障碍之间的关联。

方法

我们对4467例PD患者进行了联合（男性+女性）和分层的全X染色体生存研究（XWSS），共进行了33406次纵向随访。认知衰退定义为整体认知障碍（GCI，简易精神状态检查表评分≤25），而运动障碍通过Hoehn和Yahr 3期（HY3）进行评估。系统地进行了表达数量性状位点（eQTL）和基因共定位分析。

结果

我们在全X染色体筛查中鉴定出40个与PD纵向进展相关的常见变异，P值<9.27×10，其中包括11个与认知衰退相关的独立位点和2个与运动障碍相关的位点。rs142724191和rs144112368变异在联合分析和仅男性分析中均与认知衰退相关。rs111708875在女性患者的运动进展方面达到全基因组显著性（风险比[HR]=3.98，95%置信区间[CI]：2.54-6.25），P值=1.84×10。所有这些变异均独立于与PD、阿尔茨海默病或路易体痴呆相关的X染色体易感位点。