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Role of DNA Methylation in Human Chronic Kidney Disease

Project of the German Research Foundation (CRC 992 “MEDEP: Medical Epigenetics”)

Duration: 2016-2020
Project leader: Anna Köttgen
Staff: Pascal Schlosser

Description

Chronic kidney disease (CKD) is a complex disease affecting ~10% of adults and has a clear heritable component. We previously used genome-wide association studies to identify multiple novel, mostly intergenic genetic risk variants for CKD, which however only explain a small proportion of the estimated heritability. Our preliminary work integrating these risk variants with cell-specific chromatin annotation maps and DNA regulatory regions suggests that their effects may be mediated by altered transcription. DNA methylation is a key regulator of transcription. Small human and animal studies have linked altered DNA methylation to CKD, but large human studies of the role of DNA methylation in CKD development and progression, especially for specific causes of CKD, are missing. This proposal will address these gaps using a combination of unbiased approaches, namely epigenome-wide association studies (EWAS) of incident CKD in ~3,000 population-based individuals and EWAS of CKD progression among >500 patients with specific CKD aetiologies, followed by integration of results with kidney cell-type specific gene expression and chromatin annotation maps and genome-wide DNA sequence variants. This will be complemented by the hypothesis-driven evaluation of candidate genes, such as the investigation of the epigenetic regulation of PKD1 in CKD patients with polycystic kidney disease. Together, these approaches will provide new insights into the contribution of epigenetic modifications to CKD in humans.