壳核灰质体积与帕金森病的潜在变异
Variants Underlying Putamen Gray Matter Volumes and Parkinson's Disease.
作者信息
Mao Qiao, Wang Xiaoping, Chen Bin, Fan Longhua, Wang Shuhong, Zhang Yong, Lin Xiandong, Cao Yuping, Wu Yun-Cheng, Ji Jiawu, Xu Jianying, Zheng Jianming, Zhang Huihao, Zheng Chengchou, Chen Wenzhong, Cheng Wenhong, Luo Xingqun, Wang Kesheng, Zuo Lingjun, Kang Longli, Li Chiang-Shan R, Luo Xingguang
机构信息
Department of Psychosomatic Medicine, People's Hospital of Deyang, Deyang, China.
Department of Neurology, Shanghai Tongren Hospital, Shanghai Jiao Tong University, Shanghai, China.
出版信息
Front Neurosci. 2020 Jun 23;14:651. doi: 10.3389/fnins.2020.00651. eCollection 2020.
BACKGROUND
Selective loss of dopaminergic neurons and diminished putamen gray matter volume (GMV) represents a central feature of Parkinson's disease (PD). Recent studies have reported specific effects of kinectin 1 gene () variants on the putamen GMV.
OBJECTIVE
To examine the relationship of variants, mRNA expression in the putamen and substantia nigra pars compacta (SNc), putamen GMV, and PD.
METHODS
We examined the associations between PD and a total of 1847 imputed single nucleotide polymorphisms (SNPs) in one discovery sample [2,000 subjects with PD vs. 1,986 healthy controls (HC)], and confirmed the nominally significant associations ( < 0.05) in two replication samples (900 PD vs. 867 HC, and 940 PD vs. 801 HC, respectively). The regulatory effects of risk variants on the mRNA expression in putamen and SNc and the putamen GMV were tested. We also quantified the expression levels of mRNA in the putamen and/or SNc for comparison between PD and HC in five independent cohorts.
RESULTS
Six replicable and two non-replicable -PD associations were identified (0.009 ≤ ≤ 0.049). The major alleles of five SNPs, including rs12880292, rs8017172, rs17253792, rs945270, and rs4144657, significantly increased risk for PD (0.020 ≤ ≤ 0.049) and putamen GMVs (19.08 ≤ β ≤ 60.38; 2.82 ≤ Z ≤ 15.03; 5.0 × 10 ≤ ≤ 0.018). The risk alleles of five SNPs, including rs8017172, rs17253792, rs945270, rs4144657, and rs1188184 also significantly increased the mRNA expression in the putamen or SNc (0.021 ≤ ≤ 0.046). The mRNA was abundant in the putamen and/or SNc across five independent cohorts and differentially expressed in the SNc between PD and HC in one cohort ( = 0.047).
CONCLUSION
There was a consistent, significant, replicable, and robust positive relationship among the variants, PD risk, mRNA expression in putamen, and putamen volumes, and a modest relation between PD risk and mRNA expression in SNc, suggesting that may play a functional role in the development of PD.
背景
多巴胺能神经元的选择性丧失和壳核灰质体积（GMV）减小是帕金森病（PD）的核心特征。最近的研究报道了驱动蛋白1基因（）变体对壳核GMV的特定影响。
目的
研究变体、壳核和黑质致密部（SNc）中mRNA表达、壳核GMV与PD之间的关系。
方法
我们在一个发现样本[2000例PD患者与1986例健康对照（HC）]中检测了PD与总共1847个推算的单核苷酸多态性（SNP）之间的关联，并在两个重复样本（分别为900例PD患者与867例HC，以及940例PD患者与801例HC）中确认了名义上显著的关联（P<0.05）。测试了风险变体对壳核和SNc中mRNA表达以及壳核GMV的调节作用。我们还在五个独立队列中对壳核和/或SNc中mRNA的表达水平进行了定量，以比较PD患者和HC之间的差异。
结果
确定了6个可重复和2个不可重复的与PD相关的关联（0.009≤P≤0.049）。包括rs12880292、rs8017172、rs17253792、rs945270和rs4144657在内的5个SNP的主要等位基因显著增加了PD风险（0.020≤P≤0.049）和壳核GMV（19.08≤β≤60.38；2.82≤Z≤15.03；5.0×10≤P≤0.018）。包括rs8017172、rs17253792、rs945270、rs4144657和rs1188184在内的5个SNP的风险等位基因也显著增加了壳核或SNc中mRNA的表达（0.021≤P≤0.046）。在五个独立队列中，mRNA在壳核和/或SNc中含量丰富，并且在一个队列中，PD患者和HC之间的SNc中mRNA表达存在差异（P = 0.047）。
结论
变体、PD风险、壳核中mRNA表达和壳核体积之间存在一致、显著、可重复且稳健的正相关关系，PD风险与SNc中mRNA表达之间存在适度关联，这表明可能在PD的发生发展中起功能性作用。
Zotero 插件