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Lack of genetic evidence for a role of SLC25A46 in alpha-synucleinopathies
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DOI：10.1177/1877718x261452773.png)
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Abstract
En 中文
<jats:sec>
<jats:title>Background</jats:title>
<jats:p>
The
<jats:italic toggle="yes">SLC25A46</jats:italic>
gene encodes a mitochondrial carrier protein previously implicated in neuropathy and optic atrophy. Biallelic variants in
<jats:italic toggle="yes">SLC25A46</jats:italic>
have been described in patients with Parkinson's disease (PD) with optic atrophy, but the evidence supporting a role in PD remains limited.
</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Objective</jats:title>
<jats:p>
To assess whether
<jats:italic toggle="yes">SLC25A46</jats:italic>
variants contribute to PD, REM sleep behavior disorder (RBD), or dementia with Lewy bodies (DLB).
</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Methods</jats:title>
<jats:p>
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
<jats:italic toggle="yes">SLC25A46</jats:italic>
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.
</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results</jats:title>
<jats:p>
No associations were observed between
<jats:italic toggle="yes">SLC25A46</jats:italic>
variants and PD, RBD, or DLB. SMR analyses revealed no evidence supporting a causal relationship between
<jats:italic toggle="yes">SLC25A46</jats:italic>
expression and PD or RBD risk. Rare variant burden analyses did not identify significant associations after multiple-testing correction across cohorts or meta-analyses.
</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Conclusion</jats:title>
<jats:p>
<jats:italic toggle="yes">SLC25A46</jats:italic>
variants showed no evidence of association, suggesting the gene does not play a major role in PD, RBD, or DLB risk.
</jats:p>
</jats:sec>
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