Genetic Determinants of Survival in Parkinson's Disease in the Asian Population

Abstract

Background Patients with Parkinson's disease (PD) have reduced life expectancy compared to the general population. Genetic variation was shown to play a role in the heterogeneity of survival for patients with PD, although the underlying genetic background remains poorly studied. Objective The aim was to explore the genetic determinants influencing the survival of PD. Methods We performed a genome‐wide association analysis using a Cox proportional hazards model in a longitudinal cohort of 1080 Chinese patients with PD. Furthermore, we built a clinical‐genetic model to predict the survival of patients using clinical variables combined with polygenic risk score (PRS) of survival of PD. Results The cohort was followed up for an average of 7.13 years, with 85 incidents of death. One locus rs12628329 (RPL3) was significantly associated with reduced survival time by ~10.8 months (P = 2.72E‐08, β = 1.79, standard error = 0.32). Functional exploration suggested this variant could upregulate the expression of RPL3 and induce apoptosis and cell death. In addition, adding PRS of survival in the prediction model substantially improved survival predictability (concordance index [Cindex]: 0.936) compared with the clinical model (Cindex: 0.860). Conclusions These findings improve the current understanding of the genetic cause of survival of PD and provide a novel target RPL3 for further research on PD pathogenesis and potential therapeutic options. Our results also demonstrate the potential utility of PRS of survival in identifying patients with shorter survival and providing personalized clinical monitoring and treatment. © 2022 International Parkinson and Movement Disorder Society.

Assessing the lack of diversity in genetics research across neurodegenerative diseases: a systematic review of the GWAS Catalog and literature

“…The largest study in East Asian populations (with exception to a study done in Japan before our review period 21 ) was conducted with Han Chinese participants, replicating loci previously identified in European populations including SNCA , LRRK2 and MCCC1 in their discovery GWAS of 14,006 participants 22 . More recent studies in Chinese populations have nominated a locus on NDN/PWRN4 associated with age at onset and a locus on RPL3 associated with reduced survival 23,24 .…”

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“…The HEK293 cells were purchased from China Center for Type Culture Collection (CCTCC), Wuhan, China and cultured as described in our previous study 14 . Cells were seeded in a six‐well plate and transfected with pCDNA3.1‐Myc‐PTPA‐WT or pCDNA3.1‐Myc‐PTPA‐M329V plasmids.…”

“…The HEK293 cells were purchased from China Center for Type Culture Collection (CCTCC), Wuhan, China and cultured as described in our previous study. 14 Cells were seeded in a six-well plate and transfected with pCDNA3.1-Myc-PTPA-WT or pCDNA3.1-Myc-PTPA-M329V plasmids. After transfection for 48 hours, cycloheximide (40 μg/mL, MCE, HY-12320) was added for the indicated time points prior to protein extraction.…”