Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidneyCitation formats

  • External authors:
  • Sushant Saluja
  • Artur Akbarov
  • Eddie Cano-Gomez
  • Michelle T. McNulty
  • Christopher Finan
  • Wojciech Wystrychowski
  • Monika Szulinska
  • Huw Thomas
  • Sanjeev Pramanik
  • Sandesh Chopade
  • Priscella R. Prestes
  • Ingrid Wise
  • Evangelos Evangelou
  • Mahan Salehi
  • Yusif Shakanti
  • Mikael Ekholm
  • Matthew Denniff
  • Felix Eichinger
  • Bradley Godfrey
  • Andrzej Antczak
  • Maciej Glyda
  • Robert Król
  • Stephen Eyre
  • Jason Brown
  • Carlo Berzuini
  • John Bowes
  • Mark Caulfield
  • Ewa Zukowska-Szczechowska
  • Joanna Zywiec
  • Pawel Bogdanski
  • Matthias Kretzler
  • Adrian S. Woolf
  • David Talavera
  • Bernard Keavney
  • Pasquale Maffia
  • Tomasz J. Guzik
  • Raymond O'Keefe
  • Gosia Trynka
  • Nilesh J Samani
  • Aroon D. Hingorani
  • Matthew G. Sampson
  • Andrew P. Morris
  • Fadi J. Charchar
  • Maciej Tomaszewski
  • Andrew Morris

Standard

Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney. / Eales, James; Jiang, Xiao; Xu, Xiaoguang; Saluja, Sushant; Akbarov, Artur; Cano-Gomez, Eddie; McNulty, Michelle T.; Finan, Christopher; Guo, Hui; Wystrychowski, Wojciech; Szulinska, Monika; Thomas, Huw; Pramanik, Sanjeev; Chopade, Sandesh; Prestes, Priscella R.; Wise, Ingrid; Evangelou, Evangelos; Salehi, Mahan; Shakanti, Yusif; Ekholm, Mikael; Denniff, Matthew; Nazgiewicz, Alicja; Eichinger, Felix; Godfrey, Bradley; Antczak, Andrzej; Glyda, Maciej; Król, Robert; Eyre, Stephen; Brown, Jason; Berzuini, Carlo; Bowes, John; Caulfield, Mark; Zukowska-Szczechowska, Ewa; Zywiec, Joanna; Bogdanski, Pawel; Kretzler, Matthias; Woolf, Adrian S.; Talavera, David; Keavney, Bernard; Maffia, Pasquale; Guzik, Tomasz J.; O'Keefe, Raymond; Trynka, Gosia; Samani, Nilesh J; Hingorani, Aroon D.; Sampson, Matthew G.; Morris, Andrew P.; Charchar, Fadi J.; Tomaszewski, Maciej; Morris, Andrew.

In: Nature Genetics, Vol. 53, No. 5, 06.05.2021, p. 630–637.

Research output: Contribution to journalArticlepeer-review

Harvard

Eales, J, Jiang, X, Xu, X, Saluja, S, Akbarov, A, Cano-Gomez, E, McNulty, MT, Finan, C, Guo, H, Wystrychowski, W, Szulinska, M, Thomas, H, Pramanik, S, Chopade, S, Prestes, PR, 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, AS, Talavera, D, Keavney, B, Maffia, P, Guzik, TJ, O'Keefe, R, Trynka, G, Samani, NJ, Hingorani, AD, Sampson, MG, Morris, AP, Charchar, FJ, Tomaszewski, M & Morris, A 2021, 'Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney', Nature Genetics, vol. 53, no. 5, pp. 630–637. https://doi.org/10.1038/s41588-021-00835-w

APA

Eales, J., Jiang, X., Xu, X., Saluja, S., Akbarov, A., Cano-Gomez, E., McNulty, M. T., Finan, C., Guo, H., Wystrychowski, W., Szulinska, M., Thomas, H., Pramanik, S., Chopade, S., Prestes, P. R., Wise, I., Evangelou, E., Salehi, M., Shakanti, Y., ... Morris, A. (2021). Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney. Nature Genetics, 53(5), 630–637. https://doi.org/10.1038/s41588-021-00835-w

Vancouver

Author

Eales, James ; Jiang, Xiao ; Xu, Xiaoguang ; Saluja, Sushant ; Akbarov, Artur ; Cano-Gomez, Eddie ; McNulty, Michelle T. ; Finan, Christopher ; Guo, Hui ; Wystrychowski, Wojciech ; Szulinska, Monika ; Thomas, Huw ; Pramanik, Sanjeev ; Chopade, Sandesh ; Prestes, Priscella R. ; Wise, Ingrid ; Evangelou, Evangelos ; Salehi, Mahan ; Shakanti, Yusif ; Ekholm, Mikael ; Denniff, Matthew ; Nazgiewicz, Alicja ; Eichinger, Felix ; Godfrey, Bradley ; Antczak, Andrzej ; Glyda, Maciej ; Król, Robert ; Eyre, Stephen ; Brown, Jason ; Berzuini, Carlo ; Bowes, John ; Caulfield, Mark ; Zukowska-Szczechowska, Ewa ; Zywiec, Joanna ; Bogdanski, Pawel ; Kretzler, Matthias ; Woolf, Adrian S. ; Talavera, David ; Keavney, Bernard ; Maffia, Pasquale ; Guzik, Tomasz J. ; O'Keefe, Raymond ; Trynka, Gosia ; Samani, Nilesh J ; Hingorani, Aroon D. ; Sampson, Matthew G. ; Morris, Andrew P. ; Charchar, Fadi J. ; Tomaszewski, Maciej ; Morris, Andrew. / Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney. In: Nature Genetics. 2021 ; Vol. 53, No. 5. pp. 630–637.

Bibtex

@article{5374cb1212a64c678090c7b849b4b1fa,
title = "Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney",
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.",
author = "James Eales and Xiao Jiang and Xiaoguang Xu and Sushant Saluja and Artur Akbarov and Eddie Cano-Gomez and McNulty, {Michelle T.} and Christopher Finan and Hui Guo and Wojciech Wystrychowski and Monika Szulinska and Huw Thomas and Sanjeev Pramanik and Sandesh Chopade and Prestes, {Priscella R.} and Ingrid Wise and Evangelos Evangelou and Mahan Salehi and Yusif Shakanti and Mikael Ekholm and Matthew Denniff and Alicja Nazgiewicz and Felix Eichinger and Bradley Godfrey and Andrzej Antczak and Maciej Glyda and Robert Kr{\'o}l and Stephen Eyre and Jason Brown and Carlo Berzuini and John Bowes and Mark Caulfield and Ewa Zukowska-Szczechowska and Joanna Zywiec and Pawel Bogdanski and Matthias Kretzler and Woolf, {Adrian S.} and David Talavera and Bernard Keavney and Pasquale Maffia and Guzik, {Tomasz J.} and Raymond O'Keefe and Gosia Trynka and Samani, {Nilesh J} and Hingorani, {Aroon D.} and Sampson, {Matthew G.} and Morris, {Andrew P.} and Charchar, {Fadi J.} and Maciej Tomaszewski and Andrew Morris",
note = "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: {\textcopyright} 2021, Crown.",
year = "2021",
month = may,
day = "6",
doi = "10.1038/s41588-021-00835-w",
language = "English",
volume = "53",
pages = "630–637",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Springer Nature",
number = "5",

}

RIS

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

VL - 53

SP - 630

EP - 637

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 5

ER -