| Title: | Lack of genetic evidence for a role of SLC25A46 in alpha-synucleinopathies. |
| Journal: | Journal of Parkinson's Disease |
| Published: | 6 Aug 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42558006/ |
| DOI: | https://doi.org/10.1177/1877718x261452773 |
Publication 21069
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Abstract
BackgroundThe 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.ObjectiveTo assess whether SLC25A46 variants contribute to PD, REM sleep behavior disorder (RBD), or dementia with Lewy bodies (DLB).MethodsWe 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.ResultsNo 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.ConclusionSLC25A46 variants showed no evidence of association, suggesting the gene does not play a major role in PD, RBD, or DLB risk.</p>
11 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 45551 | Mechanistic modelling of neurodevelopment, neuroplasticity, and neurodegeneration |
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