Abstract
BackgroundDNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach.MethodsThe study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses.ResultsWe identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development.ConclusionsWe uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.
Highlights
DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate, a measure of kidney function
Identified differentially methylated positions (DMPs) showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development
We uncovered trans-ethnic and ethnic-specific DMPs associated with estimated glomerular filtration rate (eGFR), including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development
Summary
DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. Reduced kidney function measured using estimated glomerular filtration rate (eGFR) defines chronic kidney disease (CKD). DNA sequence variation accounts for 7.6% of the estimated heritability of eGFR in trans-ethnic genome-wide association studies (GWAS) [4]. Epigenetic modifications of the genome such as DNA methylation (DNAm) are heritable and contribute to gene regulation. DNAm is influenced by lifetime exposures and may provide clues on ethnic-specific differences influencing eGFR. Differential DNAm at CpG sites can be studied using microarrays with reasonable genome-wide coverage through epigenome-wide association studies (EWAS) [5, 6]
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