Cross-ancestry genome-wide association study identifies new susceptibility genes for preeclampsia

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.