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

Amber Emmett; Xiaoguang Xu; Xiao Jiang; Shadi Hames-Fathi; David Scannali; James Eales; Ewa Miller‐Kasprzak; Polly J. Downton; Antony D. Adamson; Yong Sun; Abigail C. Lay; David Talavera; Matthew J. Denniff; John Dormer; Grzegorz Rempega; Robert Król; Sébastien Rubin; Joanna Żywiec; Wojciech Wystrychowski; Paweł Bogdański; Cristian Pattaro; Nilesh J. Samani; Bernard D. Keavney; Tomasz Jan Guzik; Rachel Lennon; Andrew P. Morris; Fadi Joseph Charchar; Maciej Tomaszewski

doi:10.64898/2026.01.15.26344229

Genetic & Genomic MedicinemedRxivJan 17, 2026

Preprint

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

Amber Emmett iD, Xiaoguang Xu iD, Xiao Jiang iD, Shadi Hames-Fathi iD, David Scannali iD, James Eales iD, Ewa Miller‐Kasprzak iD, Polly J. Downton iD, Antony D. Adamson iD, Yong Sun, Abigail C. Lay iD, David Talavera iD, Matthew J. Denniff, John Dormer iD, Grzegorz Rempega iD, Robert Król iD, Sébastien Rubin iD, Joanna Żywiec iD, Wojciech Wystrychowski iD, Paweł Bogdański iD, Cristian Pattaro iD, Nilesh J. Samani iD, Bernard D. Keavney iD, Tomasz Jan Guzik iD, Rachel Lennon iD, , Maciej Tomaszewski iD

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).

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