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

IF 7.6

Movement disorders : official journal of the Movement Disorder Society Pub Date : 2025-06-03 DOI:10.1002/mds.30252

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

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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^-6, 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^-9. 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.

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X染色体相关位点与帕金森病进展的遗传分析。

背景：X染色体上的遗传变异与帕金森病（PD）的易感性有关，但它们在疾病进展中的作用尚不清楚。目的：本研究探讨X染色体变异与帕金森病患者纵向认知能力下降或运动障碍之间的关系。方法：我们对4467例PD患者进行了联合（男性+女性）和分层x染色体生存研究（XWSS），共进行了33,406次纵向访问。认知能力下降被定义为整体认知障碍（GCI， Mini Mental State Exam得分≤25），而运动障碍被定义为Hoehn and Yahr阶段3 （HY3）。系统地进行了表达、数量性状位点（eQTL）和遗传共定位分析。结果：我们在x染色体全筛查中发现了40个与PD纵向进展相关的常见变异，p值为-6，包括11个与认知能力下降相关的独立基因座和2个与运动障碍相关的独立基因座。rs142724191和rs144112368变异在联合分析和仅男性分析中都与认知能力下降有关。rs111708875基因在女性患者的运动进展中达到全基因组显著性（风险比[HR] = 3.98, 95%可信区间[CI]: 2.54-6.25）， p值= 1.84 × 10-9。所有这些变异与PD、阿尔茨海默病或路易体痴呆相关的X染色体易感位点无关。结论：我们的XWSS在PD的X染色体上发现了新的遗传进展相关位点，为PD的X染色体相关遗传基础提供了新的见解。©2025国际帕金森和运动障碍学会。

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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Movement disorders : official journal of the Movement Disorder Society

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