Investigating the Protective Role of the Mitochondrial 2158 T > C Variant in Parkinson’s Disease

Hudson et al. proposed a protective role of two mitochondrial DNA variants in PD etiology. In an array-based genotyping study, the authors showed that the m.2158 T > C (p.Lys4Arg, rs41349444) variant in SHLP2 is associated with reduced risk for PD (P-value = 2 × 10−2, OR = 0.32). A follow-up functional study by Kim et al. demonstrated that the mutated protein was protective against mitochondrial dysfunction in both in vitro and in vivo models of PD. Nevertheless, the association of this variant with reduced risk of PD has not been confirmed in large-scale sequencing datasets. To further investigate the association between m.2158 T > C and PD, we conducted an extensive genetic characterization utilizing large-scale genome sequencing (GS) datasets, totaling 4358 PD cases and 16,609 controls.