A meta-analysis of immune-cell fractions at high resolution reveals novel associations with common phenotypes and health outcomes

Qi Luo, Varun B. Dwaraka, Qingwen Chen, Huige Tong, Tianyu Zhu, Kirsten Seale, Joseph M. Raffaele, Shijie C. Zheng, Tavis L. Mendez, Yulu Chen, Natalia Carreras, Sofina Begum, Kevin Mendez, Sarah Voisin, Nir Eynon, Jessica A. Lasky-Su, Ryan Smith, Andrew E. Teschendorff

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)


Background: Changes in cell-type composition of tissues are associated with a wide range of diseases and environmental risk factors and may be causally implicated in disease development and progression. However, these shifts in cell-type fractions are often of a low magnitude, or involve similar cell subtypes, making their reliable identification challenging. DNA methylation profiling in a tissue like blood is a promising approach to discover shifts in cell-type abundance, yet studies have only been performed at a relatively low cellular resolution and in isolation, limiting their power to detect shifts in tissue composition. Methods: Here we derive a DNA methylation reference matrix for 12 immune-cell types in human blood and extensively validate it with flow-cytometric count data and in whole-genome bisulfite sequencing data of sorted cells. Using this reference matrix, we perform a directional Stouffer and fixed effects meta-analysis comprising 23,053 blood samples from 22 different cohorts, to comprehensively map associations between the 12 immune-cell fractions and common phenotypes. In a separate cohort of 4386 blood samples, we assess associations between immune-cell fractions and health outcomes. Results: Our meta-analysis reveals many associations of cell-type fractions with age, sex, smoking and obesity, many of which we validate with single-cell RNA sequencing. We discover that naïve and regulatory T-cell subsets are higher in women compared to men, while the reverse is true for monocyte, natural killer, basophil, and eosinophil fractions. Decreased natural killer counts associated with smoking, obesity, and stress levels, while an increased count correlates with exercise and sleep. Analysis of health outcomes revealed that increased naïve CD4 + T-cell and N-cell fractions associated with a reduced risk of all-cause mortality independently of all major epidemiological risk factors and baseline co-morbidity. A machine learning predictor built only with immune-cell fractions achieved a C-index value for all-cause mortality of 0.69 (95%CI 0.67–0.72), which increased to 0.83 (0.80–0.86) upon inclusion of epidemiological risk factors and baseline co-morbidity. Conclusions: This work contributes an extensively validated high-resolution DNAm reference matrix for blood, which is made freely available, and uses it to generate a comprehensive map of associations between immune-cell fractions and common phenotypes, including health outcomes.

Original languageEnglish
Article number59
Number of pages24
JournalGenome Medicine
Issue number1
Publication statusPublished - Dec 2023


  • Aging
  • Cancer
  • Covid-19
  • Disease risk factors
  • Epigenetic clocks
  • Immune system
  • Mortality
  • Obesity
  • Sex

Cite this