Proteome-wide Mendelian randomization identifies causal plasma proteins in lung cancer

iScience. 2024 Jan 20;27(2):108985. doi: 10.1016/j.isci.2024.108985. eCollection 2024 Feb 16.


Plasma proteins are promising biomarkers and potential drug targets in lung cancer. To evaluate the causal association between plasma proteins and lung cancer, we performed proteome-wide Mendelian randomization meta-analysis (PW-MR-meta) based on lung cancer genome-wide association studies (GWASs), protein quantitative trait loci (pQTLs) of 4,719 plasma proteins in deCODE and 4,775 in Fenland. Further, causal-protein risk score (CPRS) was developed based on causal proteins and validated in the UK Biobank. 270 plasma proteins were identified using PW-MR meta-analysis, including 39 robust causal proteins (both FDR-q < 0.05) and 78 moderate causal proteins (FDR-q < 0.05 in one and p < 0.05 in another). The CPRS had satisfactory performance in risk stratification for lung cancer (top 10% CPRS:Hazard ratio (HR) (95%CI):4.33(2.65-7.06)). The CPRS [AUC (95%CI): 65.93 (62.91-68.78)] outperformed the traditional polygenic risk score (PRS) [AUC (95%CI): 55.71(52.67-58.59)]. Our findings offer further insight into the genetic architecture of plasma proteins for lung cancer susceptibility.

Keywords: Bioinformatics; Cancer; Omics.