Genetic Modifiers of Parkinson's Disease: A Case-Control Study.

IF 3.9 2区医学 Q1 CLINICAL NEUROLOGY

Annals of Clinical and Translational Neurology Pub Date : 2025-09-10 DOI:10.1002/acn3.70176

Matthew J Kmiecik, Michael V Holmes, Pierre Fontanillas, Giulietta M Riboldi, Ruth B Schneider, Jingchunzi Shi, Anna Guan, Susana Tat, Steven Micheletti, Keaton Stagaman, Josh Gottesman, David A Hinds, Joyce Y Tung, Stella Aslibekyan, Lucy Norcliffe-Kaufmann

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引用次数: 0

Abstract

Objective: To examine the associations of LRRK2 p.G2019S, GBA1 p.N409S, polygenic risk scores (PRS), and APOE E4 on PD penetrance, risk, and symptoms.

Methods: We conducted a US-based observational case-control study using data from the 23andMe Inc. and Fox Insight Genetic Substudy (FIGS) databases. The total cohort included 7,586,842 participants (n = 35,163 PD); 8791 LRRK2 p.G2019S carriers (565 with PD), 37,427 GBA1 p.N409S carriers (524 with PD), 244 dual LRRK2/GBA1 carriers (37 with PD), and 7.5 million noncarriers (34,037 with PD). PRS was calculated from the most recently published European genome-wide association study. Survival models estimated the cumulative incidence of PD. Logistic regressions estimated the relative odds of reporting motor and non-motor symptoms according to genetic exposure.

Results: By the age of 80 years, the cumulative incidence of PD was 30% for dual carriers, 24% for LRRK2 p.G2019S carriers, 4% for GBA1 p.N409S carriers, and 2% for noncarriers. Higher PRS was associated with increased penetrance of the variants and earlier time to PD diagnosis. GBA1 p.N409S PD was associated with the highest burden of non-motor symptoms, including REM sleep behavior disorder and cognitive/memory deficits, and LRRK2 p.G2019S with the lowest. APOE E4 dosage was associated with greater odds of reporting hallucinations and cognitive impairment in addition to carrier status.

Interpretation: Our findings support the use of genetic screening to enrich candidate selection for neuroprotective trials and better define outcome measures based on genetics.

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帕金森病的遗传修饰因子：一项病例对照研究

目的：探讨LRRK2 p.G2019S、GBA1 p.N409S、多基因风险评分（PRS）和APOE E4与PD外显率、风险和症状的关系。方法：我们使用来自23andMe Inc.和Fox Insight遗传亚研究（FIGS）数据库的数据进行了一项美国观察性病例对照研究。总队列包括7,586,842名参与者（n = 35163名PD）；LRRK2 p.G2019S携带者8791人（565人患有PD）， GBA1 p.N409S携带者37427人（524人患有PD）， LRRK2/GBA1双携带者244人（37人患有PD），非携带者750万人（34037人患有PD）。PRS是根据最近发表的欧洲全基因组关联研究计算出来的。生存模型估计PD的累积发病率。Logistic回归估计了根据基因暴露报告运动和非运动症状的相对几率。结果：到80岁时，双携带者PD的累积发病率为30%，LRRK2 p.G2019S携带者为24%，GBA1 p.N409S携带者为4%，非携带者为2%。较高的PRS与变异外显率的增加和PD诊断的早期时间相关。GBA1 p.N409S PD与非运动症状负担最重，包括REM睡眠行为障碍和认知/记忆缺陷，而LRRK2 p.n 2019s与非运动症状负担最低。APOE E4的剂量与报告幻觉和认知障碍的几率增加有关。解释：我们的研究结果支持使用遗传筛查来丰富神经保护试验的候选人选择，并更好地定义基于遗传学的结果测量。

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

Annals of Clinical and Translational Neurology Medicine-Neurology (clinical)

CiteScore

9.10

自引率

1.90%

发文量

218

审稿时长

8 weeks

期刊介绍： Annals of Clinical and Translational Neurology is a peer-reviewed journal for rapid dissemination of high-quality research related to all areas of neurology. The journal publishes original research and scholarly reviews focused on the mechanisms and treatments of diseases of the nervous system; high-impact topics in neurologic education; and other topics of interest to the clinical neuroscience community.