A University of Pennsylvania-led team has identified hundreds of kidney disease risk loci, bringing in additional epigenetic, gene expression, single-cell, and functional data to dig into some of the genes, pathways, and cell types behind the genetic associations.

“[W]e report a comprehensive analysis of the genetic determinant of human kidney function and show the key role of epigenetic changes mediating phenotype development,” corresponding author Katalin Susztak, a nephrologist, medicine and genetics researcher at the University of Pennsylvania, and her colleagues wrote.

For their study, published in Nature Genetics on Thursday, the researchers started by analyzing published, publicly available genome-wide association study data in a meta-analysis focused on kidney function-related variants in some 1.5 million individuals. Their search led to more than 750 known kidney disease-associated variants and 126 risk variants not linked to kidney disease in the past.

From there, the team performed a series of analyses aimed at interpreting the consequences of the kidney disease-associated variants, linking nearly 90 percent of the risk loci to target genes with additional expression quantitative trait locus and methylation quantitative trait locus data.

In particular, the investigators brought together eQTL profiles from large studies such as the Genotype-Tissue Expression project for a kidney eQTL meta-analysis spanning 686 samples, which they set against risk variants found in the GWAS.

Likewise, the team used a combination of array-based genotyping and methylation profiling to map meQTL patterns in 443 kidney samples and analyzed single-cell open chromatin features in more than 57,200 individual kidney cells to look at ties between genotype, methylation, and regulatory features in the kidney.

Together, the analyses pointed to particularly pronounced DNA methylation effects on kidney disease heritability relative to heritability that was traced back to gene expression effects, the authors noted. They also saw enhanced effects in certain kidney cell types, tissues, or processes, including pathways related to metabolism or cell death, as well as impacts on proximal tubules in the kidney.

The investigators also delved deeper into one locus, looking at risk variants in and around the SLC47A1 gene on chromosome 17. They untangled causal contributions for the creatinine transport-related gene in kidney disease with a phenome-wide association study that included almost 32,300 exome-sequenced UK Biobank participants. The analysis, and a follow-up phenome-wide association study on BioMe Biobank participants, suggested that rare, loss-of-function mutations in SLC47A1 are linked to renal phenotypes such as acute renal failure or dialysis.

The team shored up those results with gene expression, mouse model, and other analyses, which highlighted the kidney injury marker and kidney disease that develop as SLC47A1 levels wane or in mice missing the gene.

“[W]e showed multiple lines of converging evidence indicating a causal role for SLC47A1 in kidney disease development,” the authors wrote, noting that their results so far suggest kidney disease risk related to the gene is “most probably acting by influencing toxin uptake and secretion of tubule epithelial cells.”