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.

Association Analysis of Essential Tremor-Associated Genetic Variants in Sporadic Late-Onset Parkinson’s Disease

“…However, there was hardly a genomicsbased large-scale study exploring this topic. In our recently published paper, we have systematically investigated the association between rare coding variants in ET-associated genes and EOPD using WES data and found a suggestive association between TENM4 and EOPD from mainland China [15]. However, EOPD represents only a small proportion of all PD cases.…”

“…A set of ET-associated genes/loci included in our analysis (Supplementary Table 2). [15]. The East Asian population evaluated the minor allele frequencies (MAF) from the public database (ExAC and gnomAD database) [23] to determine rare variants (MAF < 1%).…”

“…A recent published genome-wide association study (GWAS) of ET revealed significant common variant overlap with PD [14]. Our previous study systematically investigated the association between rare coding variants in ET-associated genes and EOPD, and found the suggestive association between teneurin transmembrane protein 4 (TENM4) and EOPD, which provided evidence for a genetic link between ET and PD [15]. In the current research, we explored the potential genetic interplay between ET-associated genetic loci/genes and LOPD from mainland China.…”

Parkinson’s disease causality and heterogeneity: a proteogenomic view

“…TENM4 encodes a transmembrane protein primarily expressed in the brain and is involved in axon guidance and central myelination 68 (Hor et al 2015). Loss-of-function and damaging missense variants in TENM4 are associated with early onset PD 69,70 (Pu et al 2020;Liang et al 2021). Accordingly, we saw significantly reduced levels of TENM4 in LRRK2+ PD patients (p=0.037).…”

Parkinsonism and tremor syndromes

“…Genetic markers, such as variants in HTRA2 gene and other genes, have been identified in few families [117][118][119]. Some PD genes have been reported to increase susceptibility for ET [115,120], while some ET-associated genes such as LINGO1 and LINGO2 variants [121] and rare TNEM4 variants [122] have been found to be associated with PD. One study, however, failed to show an increased risk of PD when examining ET-associated polymorphisms in SLC1A2, LINGO1, and PPARGC1A [123].…”