Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease

Area of Science:

• Genetics
• Epigenetics
• Nephrology

Background:

• Kidney disease affects over 800 million globally, with underlying mechanisms poorly understood.
• Genetic factors significantly influence kidney function, but specific associations and their functional consequences require further elucidation.

Purpose of the Study:

• To define genetic associations with kidney function across a large population.
• To integrate multi-omics data (methylome, transcriptome, epigenome) to identify causal genes and cellular mechanisms of kidney dysfunction.
• To prioritize target genes for identified kidney function loci.

Main Methods:

• Genome-wide association study (GWAS) in 1.5 million individuals.
• Epigenomic profiling: methylome (443 kidneys), transcriptome (686 samples), and single-cell open chromatin (57,229 kidney cells).
• Multi-stage gene prioritization strategy and functional validation in mouse models and human subjects.

Main Results:

• Identified 878 genetic loci associated with kidney function, including 126 novel loci.
• Methylation variation explained a greater proportion of heritability than gene expression.
• Prioritized target genes for 87% of kidney function loci, highlighting proximal tubules and metabolism.
• Confirmed the causal role of SLC47A1 in kidney disease through genetic studies in mice and humans.

Conclusions:

• Epigenomic data, particularly single-cell resolution, is crucial for translating GWAS findings into causal gene identification and understanding complex trait mechanisms.
• Metabolism and proximal tubule function are central to kidney function regulation.
• This study provides a framework for integrating multi-omics data to unravel kidney disease pathogenesis.