Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney

Eales, J. M. et al. (2021) Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney. Nature Genetics, 53(5), pp. 630-637. (doi: 10.1038/s41588-021-00835-w) (PMID:33958779)

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Abstract

The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.

Item Type:Articles
Additional Information:This work was supported by British Heart Foundation project grants no. PG/17/35/33001 and no. PG/19/16/34270 and Kidney Research UK grants no. RP_017_20180302 and no. RP_013_20190305 to M.T., National Institutes of Health (NIH) grant no. R01 DK117445-01A1 to A.P.M., NIH (USA) NIDDK grants no. R01 DK108805 and no. R01 DK119380 to M.G.S., British Heart Foundation Personal Chair CH/13/2/30154 and Manchester Academic Health Science Centre: Tissue Bank Grant to B.K., and Medical University of Silesia grants no. KNW-1-152/N/7/K to J.Z. and no. KNW-1-171/N/6/K to W.W. T.J.G. acknowledges support from the European Research Council (ERC-CoG-Inflammatension grant no. 726318) and the European Commission/Narodowe Centrum Badan i Rozwoju, Poland (EraNet-CVD-Plaquefight). P.M. acknowledges support of British Heart Foundation grant no. PG/19/84/34771. D.T. acknowledges support of Medical Research Council New Investigator Research Grant no. MR/R010900/1. B.K. is supported by a British Heart Foundation Personal Chair. G.T. is supported by the Wellcome Trust (grant no. WT206194) and Open Targets. E.C.-G. is supported by a Gates Cambridge Scholarship (no. OPP1144). The Nephrotic Syndrome Study Network Consortium (NEPTUNE), U54-DK-083912, is a part of the NIH Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the NIH Office of Rare Diseases Research, the National Center for Advancing Translational Sciences and the National Institute of Diabetes, Digestive, and Kidney Diseases. Additional funding and/or programmatic support for this project has also been provided by the University of Michigan, NephCure Kidney International and the Halpin Foundation. Access to TCGA kidney and GTEx data has been granted by the NIH (approvals 50804-2 and 50805-2). The results published here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics funded by the Wellcome Trust (grant reference no. 203141/Z/16/Z) for the generation and initial processing of sequencing data.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Maffia, Professor Pasquale and Guzik, Professor Tomasz
Authors: Eales, J. M., Jiang, X., Xu, X., Saluja, S., Akbarov, A., Cano-Gamez, E., McNulty, M. T., Finan, C., Guo, H., Wystrychowski, W., Szulinska, M., Thomas, H. B., Pramanik, S., Chopade, S., Prestes, P. R., Wise, I., Evangelou, E., Salehi, M., Shakanti, Y., Ekholm, M., Denniff, M., Nazgiewicz, A., Eichinger, F., Godfrey, B., Antczak, A., Glyda, M., Król, R., Eyre, S., Brown, J., Berzuini, C., Bowes, J., Caulfield, M., Zukowska-Szczechowska, E., Zywiec, J., Bogdanski, P., Kretzler, M., Woolf, A. S., Talavera, D., Keavney, B., Maffia, P., Guzik, T. J., O’Keefe, R. T., Trynka, G., Samani, N. J., Hingorani, A., Sampson, M. G., Morris, A. P., Charchar, F. J., and Tomaszewski, M.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Nature Genetics
Publisher:Nature Research
ISSN:1061-4036
ISSN (Online):1546-1718
Published Online:06 May 2021

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