PLXNA1 中罕见变异的筛选和负担分析在帕金森病中的作用。
Rare variant screening and burden analysis of PLXNA1 in Parkinson's disease.
机构信息
Department of Neurology, Laboratory of Neurodegenerative Disorders, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
出版信息
Eur J Neurol. 2022 Dec;29(12):3737-3741. doi: 10.1111/ene.15512. Epub 2022 Jul 29.
BACKGROUND AND PURPOSE
Recently, p.Glu1121Ter in PLXNA1 was identified as a potential cause of parkinsonism. However, no further replication has been conducted in a wider range of Parkinson's disease (PD) cohorts. We aimed to evaluate the genetic role of PLXNA1 in PD.
METHODS
We systematically analyzed the rare protein-coding variants (minor allele frequency [MAF] < 0.01) in 1080 patients and 1051 healthy controls. Fisher's exact test was used to analyze the associations between each variant and risk of PD, while, at gene level, over-representation of rare variants in patients was examined using the optimized sequence kernel association test (SKAT-O).
RESULTS
In total, 43 rare variants were identified in PD. No variant was significantly associated with risk of PD. Burden analysis showed enrichment of ultra-rare variants (MAF < 0.001) of PLXNA1 in PD. One patient carried a variant (p.E1121D) in the same amino acid as that in the original study. Both patients showed worsened motor symptoms, and developed dyskinesia during follow-up.
CONCLUSIONS
Our study explored the rare variant of PLXNA1 in PD, and paves the way for future research on the genetic role of PLXNA1 in PD.
背景与目的
最近，PLXNA1 中的 p.Glu1121Ter 被鉴定为帕金森病的潜在病因。然而，尚未在更广泛的帕金森病（PD）队列中进行进一步的复制。我们旨在评估 PLXNA1 在 PD 中的遗传作用。
方法
我们系统地分析了 1080 名患者和 1051 名健康对照者的 1080 名患者和 1051 名健康对照者的罕见蛋白编码变异体（次要等位基因频率[MAF]<0.01）。Fisher 确切检验用于分析每个变异体与 PD 风险之间的关联，而在基因水平上，使用优化的序列核关联测试（SKAT-O）检查患者中罕见变异体的过度表达。
结果
总共在 PD 中发现了 43 个罕见变异体。没有变异体与 PD 的风险显著相关。负担分析显示 PLXNA1 的超罕见变异体（MAF < 0.001）在 PD 中富集。一名患者携带与原始研究中相同氨基酸的变异体（p.E1121D）。两名患者的运动症状恶化，随访期间出现运动障碍。
结论
本研究探讨了 PD 中 PLXNA1 的罕见变异体，为 PLXNA1 在 PD 中的遗传作用的进一步研究铺平了道路。
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