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Prioritizing Parkinson’s disease genes using population-scale transcriptomic data

Li, Yang I., Wong, Garrett, Humphrey, Jack, Raj, Towfique·2019·Nature Communications
DOI 10.1038/s41467-019-08912-9PMC PMC6397174

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Abstract

Genome-wide association studies (GWAS) have identified over 41 susceptibility loci associated with Parkinson’s Disease (PD) but identifying putative causal genes and the underlying mechanisms remains challenging. Here, we leverage large-scale transcriptomic datasets to prioritize genes that are likely to affect PD by using a transcriptome-wide association study (TWAS) approach. Using this approach, we identify 66 gene associations whose predicted expression or splicing levels in dorsolateral prefrontal cortex (DLFPC) and peripheral monocytes are significantly associated with PD risk. We uncover many novel genes associated with PD but also novel mechanisms for known associations such as MAPT , for which we find that variation in exon 3 splicing explains the common genetic association. Genes identified in our analyses belong to the same or related pathways including lysosomal and innate immune function. Overall, our study provides a strong foundation for further mechanistic studies that will elucidate the molecular drivers of PD.

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  • Upregulated genes in chronological aging showed overrepresentation for genes in AD or PD GWAS loci, but not for genes in SCZ or BD.

    “The upregulated genes in chronological aging showed overrepresentation for genes in AD (e.g. MS4A6A, FCER1G, and CR1) or PD (e.g. BST1, PTPN22, and TNFSF13) GWAS loci, but not for genes in schizophrenia (SCZ) or bipolar disorder (BD) (Fig. 3d).”

    From Genetic analysis of the human microglial transcriptome across brain regions, aging and disease pathologies (2022) · cites this paper as [38]

    The Results section reports enrichment of PD GWAS signals near genes expressed in particular tissues and among molecular QTLs, not among genes upregulated with chronological aging. Searches for chronological aging, the named genes, and SCZ/BD comparisons found no passage in our copy addressing the claimed four-disorder comparison; page numbers were not available. (LLM, conf=0.73)

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Cited by

Sorted by citations

Authors
Li, Y. I., Wong, G., Humphrey, J., & Raj, T.
ORCID
Humphrey, Jack
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2019-03-01
Volume
10
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-019-08912-9
PMC
PMC6397174
Cited by
153
References
16
Language
en
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