Evaluation of common and rare variants of Alzheimer's disease-causal genes in Parkinson's disease
Evaluation of common and rare variants of Alzheimer's disease-causal genes in Parkinson's disease
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评估帕金森病中阿尔茨海默病致病基因的常见和罕见变异
DOI：
10.1016/j.parkreldis.2022.02.016
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Jifeng Guo
中科院分区：
文献类型：
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作者：
Qian Zeng;Hongxu Pan;Yuwen Zhao;Yunpeng Wang;Qian Xu;Jieqiong Tan;Xinxiang Yan;Jinchen Li;Beisha Tang;Jifeng Guo
帕金森病（PD）和阿尔茨海默病（AD）是老年人中最常见的神经退行性疾病。近期，在帕金森病中已报道了一些阿尔茨海默病致病基因（APP、PSEN1、PSEN2）的变异体。在本研究中，我们在中国的一个大型人群队列中研究了阿尔茨海默病致病基因的编码变异体与帕金森病之间的关联。我们对1917例早发性或家族性帕金森病患者和1652例对照进行了全外显子组测序（WES），对1962例散发性晚发性帕金森病患者和1279例对照进行了全基因组测序（WGS）。通过回归分析和优化的序列核关联检验对遗传和表型数据进行了分析。通过费舍尔精确检验进行了进一步的验证研究。我们发现PSEN2基因中的rs75733498与早发性或家族性帕金森病显著相关；然而，rs75733498与散发性晚发性帕金森病之间未发现显著关系。验证研究的结果仍然显示rs75733498与帕金森病之间存在显著关联。当仅考虑有害错义变异体（p = 0.018）或与功能缺失变异体相结合（p = 0.029）时，我们观察到APP基因与早发性或家族性帕金森病之间存在提示性关联。进一步的表型分析未显示出任何显著关联。我们的结果支持阿尔茨海默病致病基因对帕金森病可能存在遗传贡献。这些发现需要进一步的遗传和功能验证，更强大的关联研究将更好地解释帕金森病的发病机制。
Parkinson's disease (PD) and Alzheimer's disease (AD) are the most common neurodegenerative diseases in the elderly. Recently, some variants of AD-causal genes (APP, PSEN1, PSEN2) have been reported in PD. In this study, we investigated the association between coding variants of AD-causal genes and PD in a large Chinese population cohort.We performed whole-exome sequencing (WES) on 1,917 patients with early-onset or familial PD and 1,652 controls, and whole-genome sequencing (WGS) on 1,962 sporadic late-onset PD and 1,279 controls. Genetic and phenotypic data were analyzed with regression analyses and the optimized sequence kernel association test. Further validation study was performed by Fisher's exact test.We found that rs75733498 in the PSEN2 gene was significantly associated with early-onset or familial PD; however, no significant relationship was discovered between rs75733498 and sporadic late-onset PD. The result of the validation study still revealed a significant association between rs75733498 and PD. We observed a suggestive association with APP gene in early-onset or familial PD when considering damaging missense variants alone (p = 0.018) or combined with loss-of-function variants (p = 0.029). Further phenotypic analysis did not demonstrate any significant associations.Our results support a possible genetic contribution of AD-causal genes to PD. These findings warrant further genetic and functional confirmation, and more powerful association studies will better decipher the mechanisms of PD.