TY - JOUR
T1 - Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney
AU - Eales, James
AU - Jiang, Xiao
AU - Xu, Xiaoguang
AU - Saluja, Sushant
AU - Akbarov, Artur
AU - Cano-Gomez, Eddie
AU - McNulty, Michelle T.
AU - Finan, Christopher
AU - Guo, Hui
AU - Wystrychowski, Wojciech
AU - Szulinska, Monika
AU - Thomas, Huw
AU - Pramanik, Sanjeev
AU - Chopade, Sandesh
AU - Prestes, Priscella R.
AU - Wise, Ingrid
AU - Evangelou, Evangelos
AU - Salehi, Mahan
AU - Shakanti, Yusif
AU - Ekholm, Mikael
AU - Denniff, Matthew
AU - Nazgiewicz, Alicja
AU - Eichinger, Felix
AU - Godfrey, Bradley
AU - Antczak, Andrzej
AU - Glyda, Maciej
AU - Król, Robert
AU - Eyre, Stephen
AU - Brown, Jason
AU - Berzuini, Carlo
AU - Bowes, John
AU - Caulfield, Mark
AU - Zukowska-Szczechowska, Ewa
AU - Zywiec, Joanna
AU - Bogdanski, Pawel
AU - Kretzler, Matthias
AU - Woolf, Adrian S.
AU - Talavera, David
AU - Keavney, Bernard
AU - Maffia, Pasquale
AU - Guzik, Tomasz J.
AU - O'Keefe, Raymond
AU - Trynka, Gosia
AU - Samani, Nilesh J
AU - Hingorani, Aroon D.
AU - Sampson, Matthew G.
AU - Morris, Andrew P.
AU - Charchar, Fadi J.
AU - Tomaszewski, Maciej
AU - Morris, Andrew
N1 - Funding Information:
M.K. reports grants from the NIH and Goldfinch Bio during the conduct of the study, and grants from AstraZeneca, Gilead, Novo Nordisk, Eli Lilly, Janssen, Merck, Elipidera, Certa and Boehringer Ingelheim, outside the submitted work.
Funding 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.
Publisher Copyright:
© 2021, Crown.
PY - 2021/5/6
Y1 - 2021/5/6
N2 - 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.
AB - 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.
U2 - 10.1038/s41588-021-00835-w
DO - 10.1038/s41588-021-00835-w
M3 - Article
SN - 1061-4036
VL - 53
SP - 630
EP - 637
JO - Nature Genetics
JF - Nature Genetics
IS - 5
ER -