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

Human Genomics

Research

Adam J. de Smith¹  Shaobo Li¹  Swe Swe Myint¹  Janine M. LaSalle²  Julia S. Mouat²  Benjamin I. Laufer²  Philip J. Lupo³  John P. Woodhouse³  Jeremy M. Schraw³ 

[1] Center for Genetic Epidemiology, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA;Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA;Perinatal Origins of Disparities Center, University of California, Davis, CA, USA;Genome Center, University of California, Davis, CA, USA;MIND Institute, University of California, Davis, CA, USA;Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA;

关键词: Down syndrome;    Congenital heart defect;    Newborn dried blood spot;    DNA methylation;    Whole-genome bisulfite sequencing;    Epigenetics;    Epigenome-wide association study;    Differentially methylated regions;    nRBC;    Hypomethylation;   

DOI  :  10.1186/s40246-023-00540-1

 received in 2023-05-17, accepted in 2023-10-02,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundCongenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs.MethodsWe used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples.ResultsWe found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples.ConclusionsA sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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