Association of rare heterozygous PLA2G6 variants with the risk of Parkinson's disease

Abstract

The PLA2G6 gene has been identified as a causative gene for autosomal recessive early-onset dystonia-parkinsonism. Possible association was reported between single heterozygous PLA2G6 mutation and the risk of Parkinson's disease (PD), which, however, remained inconclusive. To clarify the effect of heterozygous PLA2G6 variants on the risk of PD, a total of 3710 patients with PD and 2636 controls of Chinese mainland population were recruited and genotyped by whole-exome sequencing or whole-genome sequencing. Variants in the PLA2G6 coding region were extracted and subjected to burden analysis using the optimal sequence kernel association test. In total, we identified 86 rare heterozygous variants in the PLA2G6 coding region, whereas no significant difference was found between cases and controls. Therefore, we found no supportive evidence for heterozygous PLA2G6 variants being a risk factor for PD in Chinese mainland population.

Introduction

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by loss of the midbrain dopaminergic neurons (Poewe et al., 2017). Although the pathogenesis remains unclear, genetic factors are recognized as important elements in PD development and progression (Blauwendraat et al., 2020; Liu et al., 2017). In the last decades, the PLA2G6 gene has been identified as a causative gene for autosomal recessive early-onset dystonia-parkinsonism (Guo et al., 2018b). The PLA2G6 gene encodes a group VIA calcium-independent phospholipase A2 beta protein (iPLA2β), an enzyme involved in homeostatic membrane phospholipid metabolism, mitochondrial integrity, and signal transduction (Aoun and Tiranti, 2015). PLA2G6 possesses 4 domains: ankyrin repeated domains, nucleotide-binding motif, lipase catalytic domain, and calmodulin-binding sites (Balsinde and Balboa, 2005).

For recessive PD-causing genes including PLA2G6, previous studies attempted to explore the role of single heterozygous variants in PD, whereas results have been largely inconclusive (Abou-Sleiman et al., 2006; Clark et al., 2006; Krohn et al., 2020; Park et al., 2015; Shi et al., 2011; Tan et al., 2010; Tomiyama et al., 2011; Yu et al., 2020). Specifically, several heterozygous PLA2G6 variants were identified in some patients with familial or idiopathic PD (Ferese et al., 2018; Gui et al., 2013; Tan et al., 2010; Tian et al., 2012), and decreased iPLA2β enzyme activity was proved in heterozygous PLA2G6 variant knock-in mice (Chiu et al., 2019). These several lines of evidence suggested a potential role of heterozygous PLA2G6 variants in PD, but there was still a lack of concrete evidence. Therefore, we assessed the heterozygous variants in the PLA2G6 coding region to clarify whether heterozygous variants of PLA2G6 may lead to the increased risk of PD.