Journal article

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

James M Eales, Xiao Jiang, Xiaoguang Xu, Sushant Saluja, Artur Akbarov, Eddie Cano-Gamez, Michelle T McNulty, Christopher Finan, Hui Guo, Wojciech Wystrychowski, Monika Szulinska, Huw B Thomas, Sanjeev Pramanik, Sandesh Chopade, Priscilla R Prestes, Ingrid Wise, Evangelos Evangelou, Mahan Salehi, Yusif Shakanti, Mikael Ekholm Show all

Nature Genetics | NATURE RESEARCH | Published : 2021

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 wit..

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University of Melbourne Researchers

Grants

Awarded by British Heart Foundation


Awarded by Medical Research Council


Awarded by NIDDK NIH HHS


Awarded by Wellcome Trust


Funding Acknowledgements

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.