Rare damaging variants in the SLC25A46 gene were recently reported to be associated with optic atrophy and parkinsonism in compound heterozygous state. Here, we comprehensively investigated the role of SLC25A46 variation in idiopathic Parkinson's disease (PD) by leveraging whole genome sequencing (WGS) and genotyping imputed data from the Global Parkinson's Genetics Program (GP2) and the Accelerating Medicines Partnership for Parkinson's disease initiative (AMP-PD). Our analyses included genotyping imputed data from 19,573 PD cases and 11,748 neurologically healthy controls of European, African Admixed, African, East Asian, Ashkenazi Jewish, Middle Eastern, Central Asian, and Latino and Indigenous people of the Americas ancestries from GP2. Additionally, we mined WGS data from 924 PD patients and 229 healthy controls, as well as 3359 PD cases and 4153 neurologically healthy controls of European ancestry from GP2 and AMP-PD, respectively. Burden analysis of rare non-synonymous variants across case-control individuals from WGS data did not find evidence of SLC25A46 association with PD. Of the four SLC25A46 variants observed, the p.K256R variant previously reported by Bitetto et al. was found in 1/3359 controls and 1/4153 cases of European ancestry but its association was not significant. In addition, we identified p.E79K/p.V211M in 1/3359 controls and 1/4153 cases, without confirmation of a putative compound heterozygosity effect due to the lack of phasing data. This variant was also identified in Admixed American/Latin American, African Admixed, Ashkenazi Jewish, and Central Asian ancestries. However, no significant enrichment in cases versus controls was observed. Our results do not support a major role for SLC25A46 in idiopathic PD in the European population or other ancestries, though our imputation results require cautious interpretation for ultra-rare variants.
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