Proteome-wide Mendelian randomization identifies causal plasma proteins in lung cancer
iScience, 2024
Li H., Du S., Dai J., Jiang Y., Li Z., Fan Q., Zhang Y., You D., Zhang R., Zhao Y., Christiani D., Shen S., Chen F.
Disease area | Application area | Sample type | Products |
---|---|---|---|
Oncology | Pathophysiology | Plasma | Olink Explore 3072/384 |
Abstract
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.