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Prioritizing Parkinson's disease risk genes in genome-wide association loci.

作者信息

Lange Lara M, Cerquera-Cleves Catalina, Schipper Marijn, Panagiotaropoulou Georgia, Braun Alice, Kraft Julia, Awasthi Swapnil, Bell Nathaniel, Posthuma Danielle, Ripke Stephan, Blauwendraat Cornelis, Heilbron Karl

机构信息

Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.

Institute of Neurogenetics, University of Luebeck, Luebeck, Germany.

出版信息

NPJ Parkinsons Dis. 2025 Apr 16;11(1):77. doi: 10.1038/s41531-025-00933-0.


DOI:10.1038/s41531-025-00933-0
PMID:40240380
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12003903/
Abstract

Many drug targets in ongoing Parkinson's disease (PD) clinical trials have strong genetic links. While genome-wide association studies (GWAS) nominate regions associated with disease, pinpointing causal genes is challenging. Our aim was to prioritize additional druggable genes underlying PD GWAS signals. The polygenic priority score (PoPS) integrates genome-wide information from MAGMA gene-level associations and over 57,000 gene-level features. We applied PoPS to East Asian and European PD GWAS data and prioritized genes based on PoPS, distance to the GWAS signal, and non-synonymous credible set variants. We prioritized 46 genes, including well-established PD genes (SNCA, LRRK2, GBA1, TMEM175, VPS13C), genes with strong literature evidence supporting a mechanistic link to PD (RIT2, BAG3, SCARB2, FYN, DYRK1A, NOD2, CTSB, SV2C, ITPKB), and genes relatively unexplored in PD. Many hold potential for drug repurposing or development. We prioritized high-confidence genes with strong links to PD pathogenesis that may represent our next-best candidates for developing disease-modifying therapeutics.

摘要
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2fc/12003903/7f272586f974/41531_2025_933_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2fc/12003903/d7ba26320e54/41531_2025_933_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2fc/12003903/84a96f368a97/41531_2025_933_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2fc/12003903/7f272586f974/41531_2025_933_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2fc/12003903/d7ba26320e54/41531_2025_933_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2fc/12003903/84a96f368a97/41531_2025_933_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a2fc/12003903/7f272586f974/41531_2025_933_Fig3_HTML.jpg

相似文献

[1]
Prioritizing Parkinson's disease risk genes in genome-wide association loci.

NPJ Parkinsons Dis. 2025-4-16

[2]
Prioritizing Parkinson's disease risk genes in genome-wide association loci.

medRxiv. 2024-12-14

[3]
Genome-wide Association Identifies Novel Etiological Insights Associated with Parkinson's Disease in African and African Admixed Populations.

medRxiv. 2023-5-7

[4]
A network-based systems genetics framework identifies pathobiology and drug repurposing in Parkinson's disease.

Res Sq. 2024-10-14

[5]
Genome-wide association study of Parkinson's disease in East Asians.

Hum Mol Genet. 2017-1-1

[6]
Parkinson's disease age at onset genome-wide association study: Defining heritability, genetic loci, and α-synuclein mechanisms.

Mov Disord. 2019-4-7

[7]
Targeted sequencing of Parkinson's disease loci genes highlights SYT11, FGF20 and other associations.

Brain. 2021-3-3

[8]
GWAS risk factors in Parkinson's disease: LRRK2 coding variation and genetic interaction with PARK16.

Am J Neurodegener Dis. 2013-11-29

[9]
Resequencing analysis of five Mendelian genes and the top genes from genome-wide association studies in Parkinson's Disease.

Mol Neurodegener. 2016-4-19

[10]
Genetic Evidence for Endolysosomal Dysfunction in Parkinson's Disease: A Critical Overview.

Int J Mol Sci. 2023-3-28

本文引用的文献

[1]
The Parkinson's disease risk gene cathepsin B promotes fibrillar alpha-synuclein clearance, lysosomal function and glucocerebrosidase activity in dopaminergic neurons.

Mol Neurodegener. 2024-11-25

[2]
Dual Drug Repurposing: The Example of Saracatinib.

Int J Mol Sci. 2024-4-22

[3]
Refining the impact of genetic evidence on clinical success.

Nature. 2024-5

[4]
Neuroscience fundamentals relevant to neuromodulation: Neurobiology of deep brain stimulation in Parkinson's disease.

Neurotherapeutics. 2024-4

[5]
Towards a Global View of Parkinson's Disease Genetics.

Ann Neurol. 2024-5

[6]
Synaptic vesicle glycoprotein 2C enhances vesicular storage of dopamine and counters dopaminergic toxicity.

Eur J Neurosci. 2024-5

[7]
Fyn, Blk, and Lyn kinase inhibitors: A mini-review on medicinal attributes, research progress, and future insights.

Bioorg Med Chem Lett. 2024-4-1

[8]
Silencing Parkinson's risk allele Rit2 sex-specifically compromises motor function and dopamine neuron viability.

NPJ Parkinsons Dis. 2024-2-23

[9]
Molecular profiling of human substantia nigra identifies diverse neuron types associated with vulnerability in Parkinson's disease.

Sci Adv. 2024-1-12

[10]
Multi-ancestry genome-wide association meta-analysis of Parkinson's disease.

Nat Genet. 2024-1

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