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Parkinson's Disease Pathogenic Variants: Cross-Ancestry Analysis and Microarray Data Validation

Hong, S.; Koretsky, M. J.; Lichtenberge, J.; Leonard, H.; Pitz, V.; Global Parkinson's Genetics Program (GP2),

2024-12-17 genetic and genomic medicine
10.1101/2024.12.16.24319097 medRxiv
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BackgroundKnown pathogenic variants in Parkinsons disease (PD) contribute to disease development but have yet to be fully explored by arrays at scale. ObjectivesThis study evaluated genotyping success of the NeuroBooster array (NBA) and determined the frequencies of pathogenic variants across ancestries. MethodWe analyzed the presence and allele frequency of 34 pathogenic variants in 28,710 PD cases, 9,614 other neurodegenerative disorder cases, and 15,821 controls across 11 ancestries within the Global Parkinsons Genetics Program dataset. Of these, 25 were genotyped on NBA and cluster plots were used to assess their quality. ResultsGenes previously predicted to have high or very high confidence of causing PD tend to have more pathogenic variants and are present across ancestry groups. Twenty-five of the 34 pathogenic variants were typed by the NBA array and classified "good" (n=12), "medium" (n=4), and "bad" (n=9) variants. ConclusionOur results confirm the likelihood that established PD genes are pathogenic and highlight the importance of ancestrally diverse research in PD. We also show the usefulness of the NBA as a reliable tool for genotyping of rare variants for PD.

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