Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function

Area of Science:

• Genetics
• Nephrology
• Genomics

Background:

• Reduced glomerular filtration rate (GFR) is a hallmark of chronic kidney disease (CKD).
• Lower estimated glomerular filtration rate (eGFR) is linked to increased cardiovascular and all-cause mortality.
• Understanding the genetic basis of eGFR is crucial for identifying therapeutic targets.

Purpose of the Study:

• To conduct a large-scale meta-analysis of genome-wide association studies (GWAS) to identify genetic loci associated with eGFR.
• To investigate the overlap of eGFR loci with those associated with diabetes.
• To explore the biological pathways and tissue-specific regulatory elements influencing eGFR.

Main Methods:

• Meta-analysis of GWAS data from 133,413 individuals, with replication in 42,166 individuals.
• Bioinformatic analysis to identify enriched gene expression and pathways.
• Chromatin state mapping and DNase I hypersensitivity analyses to assess variant regulatory roles.

Main Results:

• Identified 53 genetic loci associated with eGFR, including 24 novel loci.
• 19 of these loci were also associated with eGFR in individuals with diabetes.
• Genes at eGFR loci showed enrichment in kidney tissues, relevant pathways (kidney development, transmembrane transport, glucose metabolism), and kidney-specific regulatory regions.

Conclusions:

• Genetic determinants of eGFR are predominantly mediated by direct effects within kidney tissue.
• The study highlights specific cell types and biological pathways critical for kidney function.
• Findings provide insights into the genetic architecture of kidney function and potential therapeutic targets for CKD.