Kuliesius Jurgis, Timmers Paul R H J, Navarro Pau, Klaric Lucija, Wilson James F
Centre for Global Health Research, Usher Institute, University of Edinburgh, 5-7 Little France Road, Edinburgh, UK.
MRC Human Genetics Unit, University of Edinburgh, Western General Hospital, Edinburgh, UK.
Commun Biol. 2025 Aug 29;8(1):1300. doi: 10.1038/s42003-025-08738-w.
Understanding the genomic basis of human proteomic variability provides powerful tools to probe potential causal relationships of proteins and disease risk, and thus to prioritise candidate drug targets. Here, we investigated 6432 plasma proteins (1533 previously unstudied in large-scale proteomic GWAS) using the SomaLogic (v4.1) aptamer-based technology in a Scottish population from the Viking Genes study. A total of 505 significant independent protein quantitative trait loci (pQTL) were found for 455 proteins in blood plasma: 382 cis- (P < 5×10) and 123 trans- (P < 6.6×10). Of these, 31 cis-pQTL were for proteins with no previous GWAS. We leveraged these pQTL to perform causal inference using bidirectional Mendelian randomisation and colocalisation against complex traits of biomedical importance. We discovered 43 colocalising associations (with a posterior probability > 80% that pQTL and complex traits share a causal variant), pointing to plausible causal roles for the proteins. These findings include hitherto undiscovered causal links of leukocyte receptor tyrosine kinase (LTK) to type-2 diabetes and beta-1,3-glucuronyltransferase (B3GAT1) to prostate cancer. These new connections will help guide the search for new or repurposed therapies. Our findings provide strong support for continuing to increase the number of proteins studied using GWAS.
了解人类蛋白质组变异的基因组基础可提供强大的工具，以探究蛋白质与疾病风险之间的潜在因果关系，从而确定候选药物靶点的优先级。在此，我们使用基于适体的SomaLogic（v4.1）技术，对来自维京基因研究的苏格兰人群中的6432种血浆蛋白（其中1533种此前未在大规模蛋白质组全基因组关联研究中进行过研究）进行了调查。在血浆中，共发现了455种蛋白质的505个显著独立蛋白质定量性状位点（pQTL）：382个顺式（P < 5×10）和123个反式（P < 6.6×10）。其中，31个顺式pQTL针对的是此前未进行过全基因组关联研究的蛋白质。我们利用这些pQTL，通过双向孟德尔随机化和与具有生物医学重要性的复杂性状的共定位分析来进行因果推断。我们发现了43个共定位关联（后验概率>80%，表明pQTL和复杂性状共享一个因果变异），这表明这些蛋白质具有合理的因果作用。这些发现包括白细胞受体酪氨酸激酶（LTK）与2型糖尿病以及β-1,3-葡糖醛酸基转移酶（B3GAT1）与前列腺癌之间迄今未被发现的因果联系。这些新的联系将有助于指导寻找新的或重新利用的治疗方法。我们的研究结果为继续增加使用全基因组关联研究方法所研究的蛋白质数量提供了有力支持。
