Unified high-resolution immune cell fraction estimation in blood tissue from birth to old age

Abstract

BackgroundBlood is composed of many different immune cell-types, whose proportions vary throughout life. If not accounted for, these variations can seriously cause confounding or hamper interpretation of DNAm-based biomarkers. Although cell-type deconvolution methods can address this challenge for cord and adult blood, there is currently no method that can be applied to blood tissue from other age groups, including infants and children. ResultsHere we construct and extensively validate a DNAm reference panel, called UniLIFE, for 19 immune cell-types, applicable to blood tissue of any age. We use UniLIFE to delineate the dynamics of immune-cell fractions from birth to old age, and to infer disease associated immune cell fraction variations in newborns, infants, children and adults. In a prospective longitudinal study of type-1 diabetes in infants and children, UniLIFE identifies differentially methylated positions that precede type-1 diabetes diagnosis and that map to diabetes related signaling pathways. In contrast to previous studies, we are able to validate these biomarker associations in an independent DNAm dataset comprising purified monocytes from monozygotic twins discordant for type-1 diabetes, but not in lymphocytes, highlighting the importance of epigenetic changes in the innate immune system in the development of type-1 diabetes. ConclusionsIn summary, we present a life course immune-cell estimator for blood tissue of any age to help improve the identification and interpretation of blood-based DNAm biomarkers for any age groups and specially for longitudinal studies that include infants and children. The UniLIFE DNAm reference panel and algorithms to estimate cell-type fractions and perform cell-type deconvolution are available from our EpiDISH Bioconductor R-package: https://bioconductor.org/packages/release/bioc/html/EpiDISH.html