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

Hongru Li; Sha Du; Jinglan Dai; Yunke Jiang; Zaiming Li; Qihan Fan; Yixin Zhang; Dongfang You; Ruyang Zhang; Yang Zhao; David C Christiani; Sipeng Shen; Feng Chen

doi:10.1016/j.isci.2024.108985

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.

Authors

Hongru Li¹, Sha Du^{1

2}, Jinglan Dai¹, Yunke Jiang¹, Zaiming Li¹, Qihan Fan¹, Yixin Zhang¹, Dongfang You^{1

3}, Ruyang Zhang^{1

4}, Yang Zhao^{1

4}, David C Christiani^{5

6}, Sipeng Shen^{1

2

4}, Feng Chen^{1

2

3}

Affiliations

¹ Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
² Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China.
³ China International Cooperation Center of Environment and Human Health, Nanjing Medical University, Nanjing 211166, China.
⁴ Key Laboratory of Biomedical Big Data of Nanjing Medical University, Nanjing 211166, China.
⁵ Department of Environmental Health, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA.
⁶ Pulmonary and Critical Care Division, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.

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.

Keywords: Bioinformatics; Cancer; Omics.