Shi Chen, Zheng Zheng, Wang Qi, Wang Chaodong, Zhang Dabao, Zhang Min, Chan Piu, Wang Xiaomin
Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
Bioinformatics Center, School of Biomedical Engineering, Capital Medical University, Beijing, China.
PLoS One. 2016 Jun 14;11(6):e0155758. doi: 10.1371/journal.pone.0155758. eCollection 2016.
Many genetic variants have been linked to familial or sporadic Parkinson's disease (PD), among which those identified in PARK16, BST1, SNCA, LRRK2, GBA and MAPT genes have been demonstrated to be the most common risk factors worldwide. Moreover, complex gene-gene and gene-environment interactions have been highlighted in PD pathogenesis. Compared to studies focusing on the predisposing effects of genes, there is a relative lack of research investigating how these genes and their interactions influence the clinical profiles of PD. In a cohort consisting of 2,011 Chinese Han PD patients, we selected 9 representative variants from the 6 above-mentioned common PD genes to analyze their main and epistatic effects on the Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and Yahr (H-Y) stage of PD. With multiple linear regression models adjusting for medication status, disease duration, gender and age at onset, none of the variants displayed significant main effects on UPDRS or the H-Y scores. However, for gene-gene interaction analyses, 7 out of 37 pairs of variants showed significant or marginally significant associations with these scores. Among these, the GBA rs421016 (L444P)×LRRK2 rs33949390 (R1628P) interaction was consistently significant in relation to UPDRS III and UPDRS total (I+II+III), even after controlling for the family-wise error rate using False Discovery Rate (FDR-corrected p values are 0.0481 and 0.0070, respectively). Although the effects of the remaining pairs of variants did not survive the FDR correction, they showed marginally significant associations with either UPDRS or the H-Y stage (raw p<0.05). Our results highlight the importance of epistatic effects of multiple genes on the determination of PD clinical profiles and may have implications for molecular classification and personalized intervention of the disease.
许多基因变异与家族性或散发性帕金森病（PD）相关，其中在PARK16、BST1、SNCA、LRRK2、GBA和MAPT基因中鉴定出的变异已被证明是全球最常见的风险因素。此外，复杂的基因-基因和基因-环境相互作用在PD发病机制中也受到了关注。与关注基因易感性作用的研究相比，相对缺乏关于这些基因及其相互作用如何影响PD临床特征的研究。在一个由2011名中国汉族PD患者组成的队列中，我们从上述6个常见PD基因中选择了9个代表性变异，以分析它们对统一帕金森病评定量表（UPDRS）和PD的Hoehn和Yahr（H-Y）分期的主要和上位效应。通过调整用药状态、病程、性别和发病年龄的多元线性回归模型，没有一个变异对UPDRS或H-Y评分显示出显著的主要效应。然而，对于基因-基因相互作用分析，37对变异中的7对与这些评分显示出显著或边缘显著的关联。其中，即使在使用错误发现率控制家族性错误率后，GBA rs421016（L444P）×LRRK2 rs33949390（R1628P）相互作用与UPDRS III和UPDRS总分（I+II+III）始终显著相关（FDR校正后的p值分别为0.0481和0.0070）。虽然其余几对变异的效应在FDR校正后未通过检验，但它们与UPDRS或H-Y分期显示出边缘显著的关联（原始p<0.05）。我们的结果强调了多个基因的上位效应在确定PD临床特征中的重要性，可能对该疾病的分子分类和个性化干预具有启示意义。
