Shan Yuping, Hu Hong, Chu Yijing
Department of Obstetrics and Gynecology, The Affiliated Hospital of Qingdao University, Qingdao, China.
Clinical Medicine, Nantong University, Nantong, China.
BMC Pregnancy Childbirth. 2025 Apr 1;25(1):379. doi: 10.1186/s12884-025-07534-y.
Preeclampsia (PE) is a heterogeneous, multi-organ pregnancy disorder that poses a significant health burden globally, with its pathogenesis remaining unclear. This study aimed to identify novel susceptibility genes for PE through a cross-ancestry genome-wide association study (GWAS).
We performed meta-analysis to summarize the PE GWAS data from the United Kingdom, Finland, and Japan. Subsequently, the multi-ancestry sum of the single-effects model was used to perform cross-ancestry fine-mapping. The functional mapping and annotation (FUMA)-expression quantitative trait loci (eQTL) mapping method, transcriptome-wide association study (TWAS)- functional summary-based imputation (FUSION) method, genome-wide complex trait analysis (GCTA)-multivariate set-based association test (mBAT)-combo method, and polygenic priority score (PoPS) method were employed to screen for candidate genes. We utilized biomarker expression level imputation using summary-level statistics (BLISS), based on summary-level protein quantitative trait loci (pQTL) data, to conduct a multi-ancestry proteome-wide association study (PWAS) analysis, followed by candidate drug prediction.
Six novel susceptibility genes associated with PE risk were identified: NPPA, SWAP70, NPR3, FGF5, REPIN1, and ACAA1. High expression of the NPPA and SWAP70 and low expression of the remaining genes were associated with a reduced risk of PE. Furthermore, we identified drugs that target NPPA, NPR3, and REPIN1.
Our study identified NPPA, SWAP70, NPR3, FGF5, REPIN1, and ACAA1 as novel genes whose predicted expression was linked to the risk of PE, offering new insights into the genetic framework of this condition.
子痫前期（PE）是一种异质性、多器官妊娠疾病，在全球范围内造成了重大的健康负担，其发病机制尚不清楚。本研究旨在通过跨祖先全基因组关联研究（GWAS）确定PE的新的易感基因。
我们进行了荟萃分析，以总结来自英国、芬兰和日本的PE GWAS数据。随后，使用单效应模型的多祖先总和进行跨祖先精细定位。采用功能定位和注释（FUMA）-表达定量性状位点（eQTL）定位方法、全转录组关联研究（TWAS）-基于功能汇总的插补（FUSION）方法、全基因组复杂性状分析（GCTA）-多变量基于集合的关联检验（mBAT）-组合方法和多基因优先级评分（PoPS）方法筛选候选基因。我们利用基于汇总水平蛋白质定量性状位点（pQTL）数据的汇总水平统计的生物标志物表达水平插补（BLISS），进行多祖先蛋白质组全关联研究（PWAS）分析，随后进行候选药物预测。
确定了6个与PE风险相关的新的易感基因：NPPA、SWAP70、NPR3、FGF5、REPIN1和ACAA1。NPPA和SWAP70的高表达以及其余基因的低表达与PE风险降低相关。此外，我们确定了靶向NPPA、NPR3和REPIN1的药物。
我们的研究确定NPPA、SWAP70、NPR3、FGF5、REPIN1和ACAA1为新基因，其预测表达与PE风险相关，为该疾病的遗传框架提供了新的见解。
