Journal Article

Integrative analysis of clinical and epigenetic biomarkers of mortality

Mengel‐From, Jonas, Sitlani, Colleen M., Kunze, Sonja, Yao, Chen, Elhadad, Mohamed Ahmed, Pankow, James S., Deary, Ian J., Hwang, Shih‐Jen, Colicino, Elena, Qu, Yishu, Huan, Tianxiao, Nguyen, Steve, Meurs, Joyce B.J., Hermann, Brenner, Soerensen, Mette, Lloyd‐Jones, Donald M., Sotoodehnia, Nona, Fornage, Myriam, Greenland, Philip, Lee, Dong Heon, Zhang, Yan, Gieger, Christian, Ferrucci, Luigi, Toshiko, Tanaka, Baccarelli, Andrea, Hou, Lifang, Schwartz, Joel, Brody, Jennifer A., Joehanes, Roby, Bandinelli, Stefania, Hill, W. David, Ma, Jiantao, Waldenberger, Melanie, Gahrib, Sina A., Hjelmborg, Jacob, Peters, Annette, Whitsel, Eric, Domingo‐Relloso, Arce, Liu, Chunyu, Bressler, Jan, Christensen, Kaare, Ochoa‐Rosales, Carolina, Debrabant, Birgit, Voortman, Trudy, Levy, Daniel, Zheng, Yinan, Baldassari, Antoine, Vokonas, Pantel

2022

Overview

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome‐wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow‐up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry‐stratified meta‐analysis of all‐cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10−7, of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm‐based prediction models for all‐cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C‐index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, PMR = 4.1 × 10−4) and negatively associated with longevity (Beta = −1.9, PMR = 0.02). Pathway analysis revealed that genes associated with mortality‐related CpGs are enriched for immune‐ and cancer‐related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk. DNA methylation (DNAm) is an important epigenetic regulatory mechanism and is associated with many diseases and with human aging. Our study demonstrated that inter‐individual variation in DNAm is associated with all‐cause mortality risk and with cause‐specific mortality. We built a prediction model by integrating DNAm with clinical risk factors and we show that doing so can improve mortality prediction.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Age / Biomarkers / Blood / cancer / Cardiovascular disease / Cardiovascular diseases / Cardiovascular Diseases - genetics / Death / Diabetes / DNA methylation / DNA Methylation - genetics / Epigenesis, Genetic / Epigenetics / Epigenomics / Gene expression / Genomes / Heart / Humans / Hypertension / KCNQ4 protein / Longevity / machine learning / Male / Meta-analysis / Mortality / Neoplasms - genetics / Potassium channels (voltage-gated) / Prediction models / Prostate cancer / Risk factors / Sensitivity analysis / Skin cancer / Womens health