Rare variant analysis of essential tremor-associated genes in early-onset Parkinson's disease

Abstract

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.

Keywords: TENM4; early-onset Parkinson’s disease; essential tremor; genetic association; rare variant.