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

James M Eales^#¹, Xiao Jiang^#¹, Xiaoguang Xu^#¹, Sushant Saluja¹, Artur Akbarov¹, Eddie Cano-Gamez², Michelle T McNulty^{3

4}, Christopher Finan⁵, Hui Guo⁶, Wojciech Wystrychowski⁷, Monika Szulinska⁸, Huw B Thomas⁹, Sanjeev Pramanik^{1

10}, Sandesh Chopade⁵, Priscilla R Prestes¹¹, Ingrid Wise¹², Evangelos Evangelou^{13

14}, Mahan Salehi¹, Yusif Shakanti¹, Mikael Ekholm^{1

15}, Matthew Denniff¹⁶, Alicja Nazgiewicz¹, Felix Eichinger¹⁷, Bradley Godfrey¹⁸, Andrzej Antczak¹⁸, Maciej Glyda¹⁹, Robert Król⁷, Stephen Eyre²⁰, Jason Brown²¹, Carlo Berzuini⁶, John Bowes²⁰, Mark Caulfield^{22

23}, Ewa Zukowska-Szczechowska²⁴, Joanna Zywiec²⁵, Pawel Bogdanski⁸, Matthias Kretzler¹⁷, Adrian S Woolf^{26

27}, David Talavera¹, Bernard Keavney^{1

28}, Pasquale Maffia^{29

30

31}, Tomasz J Guzik^{30

32}, Raymond T O'Keefe⁹, Gosia Trynka^{2

33}, Nilesh J Samani^{16

34}, Aroon Hingorani⁵, Matthew G Sampson^{3

4

35}, Andrew P Morris^{20

36}, Fadi J Charchar^{11

16

37}, Maciej Tomaszewski^{38

39}

Affiliations

¹ Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
² Department of Human Genetics, Wellcome Sanger Institute, Cambridge, UK.
³ Division of Nephrology, Boston Children's Hospital, Boston, MA, USA.
⁴ The Broad Institute, Cambridge, MA, USA.
⁵ Institute of Cardiovascular Science, University College London, London, UK.
⁶ Centre for Biostatistics, School of Health Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
⁷ Department of General, Vascular and Transplant Surgery, Medical University of Silesia, Katowice, Poland.
⁸ Department of Obesity, Metabolic Disorders Treatment and Clinical Dietetics, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
⁹ Division of Evolution and Genomic Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
¹⁰ East Lancashire Hospitals NHS Trust, Blackburn, UK.
¹¹ Health Innovation and Transformation Centre, School of Science, Psychology and Sport, Federation University Australia, Ballarat, Victoria, Australia.
¹² Australian Institute of Tropical Health & Medicine, James Cook University, Cairns, Queensland, Australia.
¹³ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
¹⁴ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
¹⁵ Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
¹⁶ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
¹⁷ Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
¹⁸ Department of Urology and Uro-oncology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
¹⁹ Department of Transplantology and General Surgery Poznan, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
²⁰ Division of Musculoskeletal and Dermatological Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
²¹ Division of Research and Innovation, Manchester University NHS Foundation Trust, Manchester, UK.
²² William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
²³ National Institute for Health Research, Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, UK.
²⁴ Department of Health Care, Silesian Medical College, Katowice, Poland.
²⁵ Department of Internal Medicine, Diabetology and Nephrology, Zabrze, Medical University of Silesia, Katowice, Poland.
²⁶ Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
²⁷ Royal Manchester Children's Hospital and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
²⁸ Division of Cardiology and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
²⁹ Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
³⁰ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
³¹ Department of Pharmacy, University of Naples Federico II, Naples, Italy.
³² Department of Internal and Agricultural Medicine, Jagiellonian University College of Medicine, Kraków, Poland.
³³ Open Targets, Wellcome Genome Campus, Cambridge, UK.
³⁴ National Institute for Health Research, Leicester Biomedical Research Centre, Leicester, UK.
³⁵ Harvard Medical School, Boston, MA, USA.
³⁶ Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
³⁷ Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
³⁸ Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK. maciej.tomaszewski@manchester.ac.uk.
³⁹ Manchester Heart Centre and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK. maciej.tomaszewski@manchester.ac.uk.

^# Contributed equally.

PMID: 33958779
DOI: 10.1038/s41588-021-00835-w

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

James M Eales et al. Nat Genet. 2021 May.

. 2021 May;53(5):630-637.

doi: 10.1038/s41588-021-00835-w. Epub 2021 May 6.

Authors

Affiliations

¹ Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
² Department of Human Genetics, Wellcome Sanger Institute, Cambridge, UK.
³ Division of Nephrology, Boston Children's Hospital, Boston, MA, USA.
⁴ The Broad Institute, Cambridge, MA, USA.
⁵ Institute of Cardiovascular Science, University College London, London, UK.
⁶ Centre for Biostatistics, School of Health Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
⁷ Department of General, Vascular and Transplant Surgery, Medical University of Silesia, Katowice, Poland.
⁸ Department of Obesity, Metabolic Disorders Treatment and Clinical Dietetics, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
⁹ Division of Evolution and Genomic Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
¹⁰ East Lancashire Hospitals NHS Trust, Blackburn, UK.
¹¹ Health Innovation and Transformation Centre, School of Science, Psychology and Sport, Federation University Australia, Ballarat, Victoria, Australia.
¹² Australian Institute of Tropical Health & Medicine, James Cook University, Cairns, Queensland, Australia.
¹³ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
¹⁴ Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
¹⁵ Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
¹⁶ Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
¹⁷ Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
¹⁸ Department of Urology and Uro-oncology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
¹⁹ Department of Transplantology and General Surgery Poznan, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
²⁰ Division of Musculoskeletal and Dermatological Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
²¹ Division of Research and Innovation, Manchester University NHS Foundation Trust, Manchester, UK.
²² William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
²³ National Institute for Health Research, Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, UK.
²⁴ Department of Health Care, Silesian Medical College, Katowice, Poland.
²⁵ Department of Internal Medicine, Diabetology and Nephrology, Zabrze, Medical University of Silesia, Katowice, Poland.
²⁶ Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
²⁷ Royal Manchester Children's Hospital and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
²⁸ Division of Cardiology and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
²⁹ Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
³⁰ Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
³¹ Department of Pharmacy, University of Naples Federico II, Naples, Italy.
³² Department of Internal and Agricultural Medicine, Jagiellonian University College of Medicine, Kraków, Poland.
³³ Open Targets, Wellcome Genome Campus, Cambridge, UK.
³⁴ National Institute for Health Research, Leicester Biomedical Research Centre, Leicester, UK.
³⁵ Harvard Medical School, Boston, MA, USA.
³⁶ Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
³⁷ Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
³⁸ Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK. maciej.tomaszewski@manchester.ac.uk.
³⁹ Manchester Heart Centre and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK. maciej.tomaszewski@manchester.ac.uk.

^# Contributed equally.

PMID: 33958779
DOI: 10.1038/s41588-021-00835-w

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.

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References

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

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

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