Integrative kidney multi-omics traces genetic drivers of chronic kidney disease to targets within the renal epigenome, transcriptome and proteome

Abstract Chronic Kidney Disease (CKD) is a complex polygenic disease. We performed genome-wide association meta-analyses of four CKD-defining traits in up to 890,000 individuals and identified 508 loci associated with at least one trait, including 237 multi-trait CKD loci. Colocalization with kidney mRNAs, proteins and methylation patterns prioritized 651 CKD kidney genes (including 330 novel candidates) at 320 CKD-defining trait loci. We discovered over-representation of CKD kidney genes within multi-trait CKD loci. CKD kidney genes which colocalized with multiple CKD-defining traits exhibited greater relevance to kidney biology, health and disease. We found evidence for genetic regulation of developmental DNA methylation patterns that determine kidney health later in life. Finally, through analysis of Isolated Hyperchlorhidrosis - a rare genetic syndrome associated with Carbonic Anhydrase 12 (a novel CKD kidney gene) - we uncovered new metabolic consequences of genetic CA12 loss (hyperuricemia, reduced kidney function) and illuminated adverse effects of CA12-inhibitors (acetazolamide).