Epigenome-wide Association Studies of Kidney Function and Chronic Kidney Disease

Project Summary

Epigenetic modifications integrate genetic and environmental influences and are therefore of interest for complex human diseases such as chronic kidney disease (CKD). We propose the discovery and replication of kidney function-associated differentially methylated CpGs in blood through EWAS (N>30,000) followed by their comprehensive characterisation with respect to CKD cause, translation to kidney tissue, gene expression, and cell types. Together, this will provide new insights into the use of DNA methylation to study CKD-related gene regulation and illuminate pathways that may contribute to adverse outcomes.

Selected project-relevant publications

• Weihs A., Chaker L., Martin T.C., …, Köttgen A., Wilson S.G., Peeters R.P., Bell J.T., Medici M. and Teumer A. (2023) Epigenome-Wide Association Study Reveals CpG Sites Associated with Thyroid Function and Regulatory Effects on KLF9. Thyroid 33, 301-311.
• Schlosser P., Scherer N., Grundner-Culemann F., Monteiro-Martins S., Haug S., Steinbrenner I., …, Sekula P., Li Y. and Köttgen A. (2023) Genetic studies of paired metabolomes reveal enzymatic and transport processes at the interface of plasma and urine. Nat Genet 55, 995-1008.
• Wielscher M., Mandaviya P.R., Kuehnel B., …, Köttgen A., Heijmans B.T., Deloukas P., Relton C., Ong K.K., Bell J.T., Boerwinkle E., Elliott P., Brenner H., Beekman M., Levy D., Waldenberger M., Chambers J.C., Dehghan A. and Järvelin M.R. (2022) DNA methylation signature of chronic low-grade inflammation and its role in cardio-respiratory diseases. Nat Commun 13, 2408.
• Steinbrenner I. and Köttgen A. (2022) A polygenic score predicts CKD across ancestries. Nat Rev Nephrol 18, 681-682.
• Schiele M.A., Lipovsek J., Schlosser P., Soutschek M., Schratt G., Zaudig M., Berberich G., Köttgen A. and Domschke K. (2022) Epigenome-wide DNA methylation in obsessive-compulsive disorder. Transl Psychiatry 12, 221.
• Schlosser P., Tin A., Matias-Garcia P.R., Thio C.H.L., Joehanes R., Liu H., …, Köttgen A. and Teumer A. (2021) Meta-analyses identify DNA methylation associated with kidney function and damage. Nat Commun 12, 7174.
• Tin A., Schlosser P., Matias-Garcia P.R., Thio C.H.L., Joehanes R., Liu H., …, Teumer A. and Köttgen A. (2021) Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. Nat Commun 12, 7173.
• Köttgen A. and Kiryluk K. (2021) New genetic insights into kidney physiology and disease. Nat Rev Nephrol 17, 85-86.
• Tin A. and Köttgen A. (2020) Genome-Wide Association Studies of CKD and Related Traits. Clin J Am Soc Nephrol 15, 1643-1656.
• Li Y., Haug S., Schlosser P., Teumer A., Tin A., Pattaro C., Köttgen A. and Wuttke M. (2020) Integration of GWAS Summary Statistics and Gene Expression Reveals Target Cell Types Underlying Kidney Function Traits. J Am Soc Nephrol 31, 2326-2340.
• Schlosser P., Li Y., Sekula P., Raffler J., Grundner-Culemann F., Pietzner M., Cheng Y., Wuttke M., Steinbrenner I., Schultheiss U.T., Kotsis F., Kacprowski T., Forer L., Hausknecht B., Ekici A.B., Nauck M., Volker U., Walz G., Oefner P.J., Kronenberg F., Mohney R.P., Kottgen M., Suhre K., Eckardt K.U., Kastenmuller G. and Kottgen A. (2020) Genetic studies of urinary metabolites illuminate mechanisms of detoxification and excretion in humans. Nat Genet 52, 167-176.
• Wuttke M., Li Y., Li M., Sieber K.B., Feitosa M.F., …, Teumer A., Kottgen A. and Pattaro C. (2019) A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nat Genet 51, 957-972.
• Tin A., Marten J., Halperin Kuhns V.L., Li Y., Wuttke M., … Woodward O.M., Vitart V. and Kottgen A. (2019) Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels. Nat Genet 51, 1459-1474.
• Teumer A., Li Y., Ghasemi S., Prins B.P., Wuttke M., Hermle T., …Hung A.M., Pattaro C. and Kottgen A. (2019) Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria. Nat Commun 10, 4130.
• Mahajan A., Taliun D., Thurner M., …, Kottgen A., Abecasis G.R., Meigs J.B., Rotter J.I., Marchini J., Pedersen O., Hansen T., Langenberg C., Wareham N.J., Stefansson K., Gloyn A.L., Morris A.P., Boehnke M. and Mccarthy M.I. (2018) Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps. Nat Genet 50, 1505-1513.
• Ko Y.A., Yi H., Qiu C., Huang S., Park J., Ledo N., Kottgen A., Li H., Rader D.J., Pack M.A., Brown C.D. and Susztak K. (2017) Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease. Am J Hum Genet 100, 940-953.
• Chu A.Y., Tin A., Schlosser P., Ko Y.A., Qiu C., Yao C., Joehanes R., Grams M.E., Liang L., Gluck C.A., Liu C., Coresh J., Hwang S.J., Levy D., Boerwinkle E., Pankow J.S., Yang Q., Fornage M., Fox C.S., Susztak K. and Kottgen A. (2017) Epigenome-wide association studies identify DNA methylation associated with kidney function. Nat Commun 8, 1286.
• Wuttke M. and Kottgen A. (2016) Insights into kidney diseases from genome-wide association studies. Nat Rev Nephrol 12, 549-562.
• Hoppmann A.S., Schlosser P., Backofen R., Lausch E. and Kottgen A. (2016) GenToS: Use of Orthologous Gene Information to Prioritize Signals from Human GWAS. PLoS One 11, e0162466.
• Pattaro C., Teumer A., Gorski M., Chu A.Y., Li M., Mijatovic V., Garnaas M., …, Köttgen A., Kao W.H., Fox C.S. (2015) Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function. Nat Commun 7, 10023.
• Kottgen A., Albrecht E., Teumer A., Vitart V., Krumsiek J., …, Ciullo M., Fox C.S., Caulfield M., Bochud M. and Gieger C. (2013) Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet 45, 145-154.
• Eckardt K.U., Coresh J., Devuyst O., Johnson R.J., Kottgen A., Levey A.S. and Levin A. (2013) Evolving importance of kidney disease: from subspecialty to global health burden. Lancet 382, 158-169.
• Pattaro C., Kottgen A., Teumer A., Garnaas M., Boger C.A., …, Chasman D.I., Kao W.H. and Fox C.S. (2012) Genome-wide association and functional follow-up reveals new loci for kidney function. PloS Genet 8, e1002584.
• Kottgen A., Pattaro C., Boger C.A., Fuchsberger C., …, Chasman D.I., Kao W.H., Heid I.M. and Fox C.S. (2010) New loci associated with kidney function and chronic kidney disease. Nat Genet 42, 376-384.