Epigenome-wide association study of kidney function identifies trans-ethnic and ethnic-specific loci.

Journal Article (Journal Article)

Background

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.

Methods

The 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.

Results

We 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.

Conclusions

We 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.

Full Text

Duke Authors

Cited Authors

  • Breeze, CE; Batorsky, A; Lee, MK; Szeto, MD; Xu, X; McCartney, DL; Jiang, R; Patki, A; Kramer, HJ; Eales, JM; Raffield, L; Lange, L; Lange, E; Durda, P; Liu, Y; Tracy, RP; Van Den Berg, D; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, TOPMed MESA Multi-Omics Working Group, ; Evans, KL; Kraus, WE; Shah, S; Tiwari, HK; Hou, L; Whitsel, EA; Jiang, X; Charchar, FJ; Baccarelli, AA; Rich, SS; Morris, AP; Irvin, MR; Arnett, DK; Hauser, ER; Rotter, JI; Correa, A; Hayward, C; Horvath, S; Marioni, RE; Tomaszewski, M; Beck, S; Berndt, SI; London, SJ; Mychaleckyj, JC; Franceschini, N

Published Date

  • April 30, 2021

Published In

Volume / Issue

  • 13 / 1

Start / End Page

  • 74 -

PubMed ID

  • 33931109

Pubmed Central ID

  • PMC8088054

Electronic International Standard Serial Number (EISSN)

  • 1756-994X

International Standard Serial Number (ISSN)

  • 1756-994X

Digital Object Identifier (DOI)

  • 10.1186/s13073-021-00877-z

Language

  • eng