Finding Potential Drug Targets for Pre‐Eclampsia Using Mendelian Randomisation and Colocalisation Analysis

ABSTRACT Introduction Pre‐eclampsia (PE) is a common complication of pregnancy and there is an urgent need for new drug targets. We performed whole proteome‐wide Mendelian randomisation (MR) and colocalisation analyses to identify potential therapeutic targets for PE. Material and Methods A two‐sample MR study was conducted using summary‐level statistics of 734 plasma proteins retrieved from large genome‐proteome‐wide association studies. The summary statistics of PE or eclampsia were obtained from the FinnGen consortium. Wald ratio and Inverse variance weighted (IVW) were used to assess the causal association between proteins and PE. Colocalisation analyses were conducted to examine whether the identified proteins and PE shared incidental variants. Results Genetically predicted circulating levels of 42 proteins were associated with PE risk after Benjamini‐Hochberg correction. Nineteen of the gene‐predicted proteins showed evidence of increased PE risk (CRELD1, CPA4, AHSG, NFASC, QDPR, NTM, PZP, FAM171B, RTN4R, FLRT2, ADH4, ADM, SPINK5, LGALS4, CKM, SPON2, UROS, CXCL10 and APOBEC3G); 23 proteins reduced the risk of PE (CLIC5, NEO1, SWAP70, KLK8, VWA2, FSTL1, CXCL11, APOB, NPPB, CNTN4, IL12B, ACHE, TCN1, GFRA2, GNMT, HPGDS, DPT, MANBA, SPARCL1, ACE, FUT8, BST1 and ACP1). Bayesian colocalisation indicated that six proteins (VWA2, ACHE, CXCL10, PZP, AHSG and UROS) and PE, which were identified as high evidence of colocalisation with PE. Conclusions This study provides evidence of the causal association between genetically predicted 42 proteins associated with PE risk, which might be promising drug targets for PE.