Rare variant analysis of essential tremor‐associated genes in early‐onset Parkinson’s disease

OBJECTIVE: Parkinson’s disease (PD) and essential tremor (ET) are the two most common movement disorders. A significant overlap in clinical features, epidemiology, imaging, and pathology suggests that PD and ET may also share common genetic risk factors. Previous studies have only assessed a limited number of ET‐associated genes in PD patients and vice versa. Consequently, the genetic association between PD and ET remains incompletely characterized. In this study, we systematically investigated a potential association between rare coding variants in ET‐associated genes and PD, in a relatively large Chinese population cohort. METHODS: To investigate the genetic association between ET and PD, we performed the sequence kernel association testing (SKAT‐O) to explore the variant burden of 33 ET‐associated genes, using whole‐exome sequencing (WES) data from 1494 early‐onset PD (EOPD) patients and 1357 control subjects from mainland China. RESULTS: We report that rare loss‐of‐function and damaging missense variants of TNEM4 are suggestively associated with EOPD (P = 0.026), damaging missense variants of TNEM4 alone are also suggestively associated with EOPD (P = 0.032). No other rare damaging variants in ET‐related genes were significantly associated with EOPD. INTERPRETATION: This is the first systematic analysis of ET‐associated genes in EOPD. The suggestive association between TNEM4 and EOPD provides new evidence for a genetic link between ET and PD.