Integration of transcriptome-wide association study with neuronal dysfunction assays provides functional genomics evidence for Parkinson's disease genes

Genome-wide association studies (GWAS) have markedly advanced our understanding of the genetics of Parkinson's disease (PD), but they currently do not account for the full heritability of PD. In many cases it is difficult to unambiguously identify a specific gene within each locus because GWAS...

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Bibliographic Details
Published in:Human molecular genetics 2023-01, Vol.32 (4), p.685-695
Main Authors: Li, Jiayang, Amoh, Bismark Kojo, McCormick, Emma, Tarkunde, Akash, Zhu, Katy Fan, Perez, Alma, Mair, Megan, Moore, Justin, Shulman, Joshua M, Al-Ramahi, Ismael, Botas, Juan
Format: Article
Language:English
Subjects:
Animals
Drosophila - genetics
Genetic Predisposition to Disease
Genome-Wide Association Study - methods
Genomics
Original
Parkinson Disease - genetics
Polymorphism, Single Nucleotide
Transcriptome - genetics
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Summary:Genome-wide association studies (GWAS) have markedly advanced our understanding of the genetics of Parkinson's disease (PD), but they currently do not account for the full heritability of PD. In many cases it is difficult to unambiguously identify a specific gene within each locus because GWAS does not provide functional information on the identified candidate loci. Here we present an integrative approach that combines transcriptome-wide association study (TWAS) with high-throughput neuronal dysfunction analyses in Drosophila to discover and validate candidate PD genes. We identified 160 candidate genes whose misexpression is associated with PD risk via TWAS. Candidates were validated using orthogonal in silico methods and found to be functionally related to PD-associated pathways (i.e. endolysosome). We then mimicked these TWAS-predicted transcriptomic alterations in a Drosophila PD model and discovered that 50 candidates can modulate α-Synuclein(α-Syn)-induced neurodegeneration, allowing us to nominate new genes in previously known PD loci. We also uncovered additional novel PD candidate genes within GWAS suggestive loci (e.g. TTC19, ADORA2B, LZTS3, NRBP1, HN1L), which are also supported by clinical and functional evidence. These findings deepen our understanding of PD, and support applying our integrative approach to other complex trait disorders.
ISSN:0964-6906
1460-2083
1460-2083
DOI:10.1093/hmg/ddac230