Exploring the Effects of Genetic Variants on Clinical Profiles of Parkinson's Disease Assessed by the Unified Parkinson's Disease Rating Scale and the Hoehn-Yahr Stage.
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.
Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.|Bioinformatics Center, School of Biomedical Engineering, Capital Medical University, Beijing, China.
Chen
C
Shi
Department of Neurobiology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China.
Zheng
Z
Zheng
Department of Statistics, Purdue University, West Lafayette, Indiana, United States of America.
Qi
Q
Wang
Department of Neurobiology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China.|Department of Neurology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China.|Department of Neurology, The Affiliated Sanming First Hospital of Fujian Medical University, Sanming, Fujian, China.
Chaodong
C
Wang
Bioinformatics Center, School of Biomedical Engineering, Capital Medical University, Beijing, China.|Department of Statistics, Purdue University, West Lafayette, Indiana, United States of America.
Dabao
D
Zhang
Bioinformatics Center, School of Biomedical Engineering, Capital Medical University, Beijing, China.|Department of Statistics, Purdue University, West Lafayette, Indiana, United States of America.|Alzheimer Disease Center of Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
Min
M
Zhang
Department of Neurobiology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China.|Department of Neurology, Beijing Institute of Geriatrics, Xuanwu Hospital of Capital Medical University, Beijing, China.|Key Laboratory on Neurodegenerative Disease of Ministry of Education and Key Laboratory on Parkinson's Disease of Beijing, Beijing, China.|Parkinson Disease Center of Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
Piu
P
Chan
Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.|Parkinson Disease Center of Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China.
Xiaomin
X
Wang
D000368:Aged; D015331:Cohort Studies; D004843:Epistasis, Genetic; D005260:Female; D059647:Gene-Environment Interaction; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*