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

被引：0

作者：

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

Matthew Denniff

Alicja Nazgiewicz

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 T. O’Keefe

Gosia Trynka

Nilesh J. Samani

Aroon Hingorani

Matthew G. Sampson

Andrew P. Morris

Fadi J. Charchar

Maciej Tomaszewski

机构：

[1] University of Manchester,Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health

[2] Wellcome Sanger Institute,Department of Human Genetics

[3] Boston Children’s Hospital,Division of Nephrology

[4] The Broad Institute,Institute of Cardiovascular Science

[5] University College London,Centre for Biostatistics, School of Health Sciences, Faculty of Medicine, Biology and Health

[6] University of Manchester,Department of General, Vascular and Transplant Surgery

[7] Medical University of Silesia,Department of Obesity, Metabolic Disorders Treatment and Clinical Dietetics

[8] Karol Marcinkowski University of Medical Sciences,Division of Evolution and Genomic Sciences, Faculty of Medicine, Biology and Health

[9] University of Manchester,Health Innovation and Transformation Centre, School of Science, Psychology and Sport

[10] Federation University Australia,Australian Institute of Tropical Health & Medicine

[11] James Cook University,Department of Epidemiology and Biostatistics, School of Public Health

[12] Imperial College London,Department of Hygiene and Epidemiology

[13] University of Ioannina Medical School,Department of Cardiovascular Sciences

[14] University of Leicester,Department of Medicine

[15] University of Michigan,Department of Urology and Uro

[16] Karol Marcinkowski University of Medical Sciences,oncology

[17] Nicolaus Copernicus University,Department of Transplantology and General Surgery Poznan, Collegium Medicum

[18] University of Manchester,Division of Musculoskeletal and Dermatological Sciences, Faculty of Medicine, Biology and Health

[19] Manchester University NHS Foundation Trust,Division of Research and Innovation

[20] Queen Mary University of London,William Harvey Research Institute, Barts and The London School of Medicine and Dentistry

[21] Queen Mary University of London,National Institute for Health Research, Barts Cardiovascular Biomedical Research Centre

[22] Silesian Medical College,Department of Health Care

[23] Medical University of Silesia,Department of Internal Medicine, Diabetology and Nephrology, Zabrze

[24] University of Manchester,Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health

[25] Manchester University NHS Foundation Trust,Royal Manchester Children’s Hospital and Manchester Academic Health Science Centre

[26] Manchester University NHS Foundation Trust,Division of Cardiology and Manchester Academic Health Science Centre

[27] University of Glasgow,Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences

[28] University of Glasgow,Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences

[29] University of Naples Federico II,Department of Pharmacy

[30] Jagiellonian University College of Medicine,Department of Internal and Agricultural Medicine

[31] Open Targets,National Institute for Health Research

[32] Wellcome Genome Campus,Department of Biostatistics, Institute of Translational Medicine

[33] Leicester Biomedical Research Centre,Department of Physiology

[34] Harvard Medical School,Manchester Heart Centre and Manchester Academic Health Science Centre

[35] University of Liverpool,Department of Clinical Sciences

[36] University of Melbourne,undefined

[37] Manchester University NHS Foundation Trust,undefined

[38] East Lancashire Hospitals NHS Trust,undefined

[39] Danderyd Hospital,undefined

[40] Karolinska Institutet,undefined

来源：

Nature Genetics | 2021年 / 53卷

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摘要：

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.

引用

页码：630 / 637

页数：7

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