在全基因组关联位点中确定帕金森病风险基因的优先级。

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

正在进行的帕金森病（PD）临床试验中的许多药物靶点都有很强的遗传关联。虽然全基因组关联研究（GWAS）确定了与疾病相关的区域，但确定因果基因具有挑战性。我们的目标是对PD GWAS信号背后的其他可成药基因进行优先级排序。多基因优先级评分（PoPS）整合了来自MAGMA基因水平关联和超过57000个基因水平特征的全基因组信息。我们将PoPS应用于东亚和欧洲的PD GWAS数据，并根据PoPS、与GWAS信号的距离以及非同义可信集变体对基因进行优先级排序。我们确定了46个基因的优先级，包括已确立的PD基因（SNCA、LRRK2、GBA1、TMEM175、VPS13C）、有强有力的文献证据支持与PD存在机制联系的基因（RIT2、BAG3、SCARB2、FYN、DYRK1A、NOD2、CTSB、SV2C、ITPKB），以及在PD中相对未被探索的基因。许多基因具有药物再利用或开发的潜力。我们确定了与PD发病机制有紧密联系的高置信度基因，这些基因可能是我们开发疾病修饰疗法的次优候选基因。