Association between NOTCH3 gene and Parkinson's disease based on whole-exome sequencing.
Association between NOTCH3 gene and Parkinson's disease based on whole-exome sequencing.
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DOI：
10.3389/fnagi.2022.995330
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发表时间：
2022
影响因子：
4.8
通讯作者：
中科院分区：
文献类型：
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常染色体显性遗传性脑动脉病伴皮质下梗塞和白质脑病(CADASIL)是一种由NOTCH3基因突变引起的遗传性脑小血管疾病。以前的研究已经在神经病理学和临床特征方面建立了NOTCH3变异与帕金森病(PD)之间的联系。在这项研究中，我们旨在探索NOTCH3基因在中国大规模队列中在帕金森病中的作用。共有1,917名早发性或家族性帕金森病患者和1,652名匹配的对照组纳入研究。根据次要等位基因频率(MAF)将所有变异分为常见或罕见类型(MAF、 >； 0.01为常见变异，其他为稀有变异)。对常见变异体用PLINK进行单变异体检验，对罕见变异体用优化序列核关联检验(SKAT-O)进行基于基因的分析。对于基因型-表型相关性评估，采用回归模型来比较研究组之间的临床特征。三种常见的变异体(rs1044006、rs1043997和rs1043994)对帕金森病有名义上的保护作用。然而，这些SNP都没有幸免于Bonferroni校正。验证队列中的结果显示，这些变异与帕金森病之间存在显著但相反的关联。对罕见变异的基因分析表明，NOTCH3与帕金森病没有明显的关联。尽管我们在随后的基因-表型分析中没有发现显著的相关性，但NOTCH3变异携带者运动症状的临床评分较高是值得关注的。我们的结果提示，NOTCH3基因在中国人早发性或家族性帕金森病中可能不起重要作用。
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary cerebral small vessel disease caused by mutations in the NOTCH3 gene. Previous studies have established a link between NOTCH3 variants and Parkinson’s disease (PD) in terms of neuropathology and clinical characteristics. In this study, we aimed to explore the role of NOTCH3 gene in PD in a large Chinese cohort. A total of 1,917 patients with early-onset or familial PD and 1,652 matched controls were included. All variants were divided into common or rare types by minor allele frequency (MAF) at a threshold of 0.01 (MAF > 0.01 into common variants and others into rare variants). Common variants were subjected to single-variant tests by PLINK, then gene-based analyses were used for rare variants with the optimized sequence kernel association test (SKAT-O). For genotype–phenotype correlation assessment, regression models were conducted to compare clinical features between the studied groups. Three common variants (rs1044006, rs1043997, and rs1043994) showed a nominal protective effect against PD. However, none of these SNPs survived Bonferroni correction. The results in the validation cohort revealed a significant but opposite association between these variants and PD. The gene-based analyses of rare variants showed no significant associations of NOTCH3 with PD. Although we did not find significant associations in the following genotype–phenotype analysis, the higher clinical scores of motor symptoms in NOTCH3-variant carriers were of interest. Our results indicated that NOTCH3 gene may not play an important role in the early-onset or familial PD of Chinese population.
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Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
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