Down Syndrome Altered Cell Composition in Blood, Brain, and Buccal Swab Samples Profiled by DNA-Methylation-Based Cell-Type Deconvolution

Abstract

Down syndrome (DS) is a genetic disorder caused by an extra copy of chromosome 21 that presents developmental dysfunction and intellectual disability. To better understand the cellular changes associated with DS, we investigated the cell composition in blood, brain, and buccal swab samples from DS patients and controls using DNA methylation-based cell-type deconvolution. We used genome-scale DNA methylation data from Illumina HumanMethylation450k and HumanMethylationEPIC arrays to profile cell composition and trace fetal lineage cells in blood samples (DS N = 46; control N = 1469), brain samples from various regions (DS N = 71; control N = 101), and buccal swab samples (DS N = 10; control N = 10). In early development, the number of cells from the fetal lineage in the blood is drastically lower in DS patients (Δ = 17.5%), indicating an epigenetically dysregulated maturation process for DS patients. Across sample types, we observed significant alterations in relative cell-type proportions for DS subjects compared with the controls. Cell-type proportion alterations were present in samples from early development and adulthood. Our findings provide insight into DS cellular biology and suggest potential cellular interventional targets for DS.

Deciphering the role of immune cell composition in epigenetic age acceleration: Insights from cell‐type deconvolution applied to human blood epigenetic clocks

“…EAA was observed in blood samples from populations with trisomy 21 (Horvath et al., 2015; Xu et al., 2022). At the same time, consistent decreases in naïve lymphocytes and increases in memory lymphocytes were observed in trisomy 21 patients (Zhang, Stolrow, et al., 2023). The direction of EAA and naïve and memory lymphocyte change suggest the immune cell composition's confounding effect on EAA in trisomy 21.…”

“…Specifically in human blood, our previous research employed differentially methylated regions identified between purified leukocyte subtypes to develop a reference‐based deconvolution algorithm, allowing estimation of the distribution of various leukocyte subtypes (Salas et al., 2022). This blood deconvolution approach has been utilized to investigate altered immune cell composition in multiple diseases, such as cancer (Chen et al., 2022, 2023), hypertension (Kresovich et al., 2023), and trisomy 21 (Zhang, Stolrow, et al., 2023).…”

Epigenomic signature of major congenital heart defects in newborns with Down syndrome

“…Moreover, nRBC proportions were estimated from DNA methylation array data, rather than using actual cell counts, and cell-type deconvolution in individuals with DS may be confounded by the presence of blast cells that are common in DS and not accounted for in the analysis [ 17 ]. Cell composition deconvoluted from DNA methylation arrays has been previously reported to be altered in DS blood compared to non-DS blood [ 64 ]. Further, we previously reported a positive relationship between high nRBC proportions in newborns with DS and the presence of somatic GATA1 mutations, indicative of transient abnormal myelopoiesis (TAM) or silent TAM, and it is possible that the relationship between CHD and global hypomethylation in males may be confounded by this preleukemic condition [ 17 ].…”