DOI: 10.1177/1877718x261452773 ISSN: 1877-7171
Lack of genetic evidence for a role of SLC25A46 in alpha-synucleinopathies
Han Yu, Sitki Cem Parlar, Konstantin Senkevich, Emma N Somerville, Zhao Zhang, Lang Liu, Meron Teferra, Jamil Ahmad, Farnaz Asayesh, Guy A Rouleau, Ziv Gan-Or
Background
The
SLC25A46
gene encodes a mitochondrial carrier protein previously implicated in neuropathy and optic atrophy. Biallelic variants in
SLC25A46
have been described in patients with Parkinson's disease (PD) with optic atrophy, but the evidence supporting a role in PD remains limited.
Objective
To assess whether
SLC25A46
variants contribute to PD, REM sleep behavior disorder (RBD), or dementia with Lewy bodies (DLB).
Methods
We examined common variants using four representative PD genome-wide association studies (GWAS) and an RBD GWAS and applied summary-data-based Mendelian randomization (SMR) to evaluate whether genetically regulated expression of
SLC25A46
shows a causal association with the risk of PD or RBD. Rare variant analyses were conducted in four cohorts of European descent: Accelerating Medicines Partnership: Parkinson's Disease (AMP-PD) PD (3,051 PD, 3,667 controls), UK Biobank (3,267 PD, 14,939 proxy, 54,800 controls), RBD (1,376 RBD, 2,580 controls), and AMP-PD DLB (2,605 DLB, 1,894 controls). Optimal sequence kernel association test (SKAT-O) and meta-analysis were used to assess rare variants.
Results
No associations were observed between
SLC25A46
variants and PD, RBD, or DLB. SMR analyses revealed no evidence supporting a causal relationship between
SLC25A46
expression and PD or RBD risk. Rare variant burden analyses did not identify significant associations after multiple-testing correction across cohorts or meta-analyses.
Conclusion
SLC25A46
variants showed no evidence of association, suggesting the gene does not play a major role in PD, RBD, or DLB risk.