Systematic integrated analysis of genetic and epigenetic variation in diabetic kidney disease

Xin Sheng, Chengxiang Qiu, Hongbo Liu, Caroline Gluck, Jesse Y. Hsu, Jiang He, Chi Yuan Hsu, Daohang Sha, Matthew R. Weir, Tamara Isakova, Dominic Raj, Hernan Rincon-Choles, Harold I. Feldman, Raymond Townsend, Hongzhe Li, Katalin Susztak*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Poor metabolic control and host genetic predisposition are critical for diabetic kidney disease (DKD) development. The epigenome integrates information from sequence variations and metabolic alterations. Here, we performed a genome-wide methylome association analysis in 500 subjects with DKD from the Chronic Renal Insufficiency Cohort for DKD phenotypes, including glycemic control, albuminuria, kidney function, and kidney function decline. We show distinct methylation patterns associated with each phenotype. We define methylation variations that are associated with underlying nucleotide variations (methylation quantitative trait loci) and show that underlying genetic variations are important drivers of methylation changes. We implemented Bayesian multitrait colocalization analysis (moloc) and summary data-based Mendelian randomization to systematically annotate genomic regions that show association with kidney function, methylation, and gene expression. We prioritized 40 loci, where methylation and gene-expression changes likely mediate the genotype effect on kidney disease development. Functional annotation suggested the role of inflammation, specifically, apoptotic cell clearance and complement activation in kidney disease development. Our study defines methylation changes associated with DKD phenotypes, the key role of underlying genetic variations driving methylation variations, and prioritizes methylome and gene-expression changes that likely mediate the genotype effect on kidney disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)29013-29024
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number46
DOIs
StatePublished - Nov 17 2020

Keywords

  • Chronic kidney disease
  • Epigenetics
  • Methylation quantitative trait loci (mQTL)
  • Multiomics integration analysis
  • Multitrait colocalization analysis (moloc)

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'Systematic integrated analysis of genetic and epigenetic variation in diabetic kidney disease'. Together they form a unique fingerprint.

Cite this