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

Alternative Splicing / genetics Blood Pressure / genetics DNA Methylation / genetics Genetic Predisposition to Disease Genetic Variation Genome-Wide Association Study Genomics Humans Hypertension / genetics Kidney / pathology Mendelian Randomization Analysis Polymorphism, Single Nucleotide / genetics Quantitative Trait Loci / genetics

Journal

Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904

Informations de publication

Date de publication:
05 2021
Historique:
received: 10 01 2020
accepted: 04 03 2021
pubmed: 8 5 2021
medline: 16 6 2021
entrez: 7 5 2021
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1038/s41588-021-00835-w PMID: 33958779
pubmed: 33958779
doi: 10.1038/s41588-021-00835-w
pii: 10.1038/s41588-021-00835-w
doi:

Banques de données

Dryad
['10.5061/dryad.15dv41nvx']

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

630-637

Subventions

Organisme : NIDDK NIH HHS
ID : U54 DK083912
Pays : United States
Organisme : Wellcome Trust
ID : WT206194
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/19/16/34270
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK117445
Pays : United States
Organisme : Medical Research Council
ID : G9521010
Pays : United Kingdom
Organisme : British Heart Foundation
ID : CH/13/2/30154
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/19/84/34771
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK119380
Pays : United States
Organisme : Wellcome Trust
ID : 203141/Z/16/Z
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : R01 DK108805
Pays : United States
Organisme : Medical Research Council
ID : MR/R010900/1
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/17/35/33001
Pays : United Kingdom

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Auteurs

James M Eales (JM)

Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
ORCID: 0000-0001-6238-5952

Xiao Jiang (X)

Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
ORCID: 0000-0002-1442-8927

Xiaoguang Xu (X)

Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
ORCID: 0000-0003-4568-1623

Sushant Saluja (S)

Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.

Artur Akbarov (A)

Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.

Eddie Cano-Gamez (E)

Department of Human Genetics, Wellcome Sanger Institute, Cambridge, UK.

Michelle T McNulty (MT)

Division of Nephrology, Boston Children's Hospital, Boston, MA, USA.
The Broad Institute, Cambridge, MA, USA.

Christopher Finan (C)

Institute of Cardiovascular Science, University College London, London, UK.
ORCID: 0000-0002-3319-1937

Hui Guo (H)

Centre for Biostatistics, School of Health Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
ORCID: 0000-0003-0282-6933

Wojciech Wystrychowski (W)

Department of General, Vascular and Transplant Surgery, Medical University of Silesia, Katowice, Poland.

Monika Szulinska (M)

Department of Obesity, Metabolic Disorders Treatment and Clinical Dietetics, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
ORCID: 0000-0002-1163-0919

Huw B Thomas (HB)

Division of Evolution and Genomic Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
ORCID: 0000-0001-9626-9706

Sanjeev Pramanik (S)

Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
East Lancashire Hospitals NHS Trust, Blackburn, UK.
ORCID: 0000-0003-2317-3628

Sandesh Chopade (S)

Institute of Cardiovascular Science, University College London, London, UK.

Priscilla R Prestes (PR)

Health Innovation and Transformation Centre, School of Science, Psychology and Sport, Federation University Australia, Ballarat, Victoria, Australia.
ORCID: 0000-0002-9034-6595

Ingrid Wise (I)

Australian Institute of Tropical Health & Medicine, James Cook University, Cairns, Queensland, Australia.

Evangelos Evangelou (E)

Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
ORCID: 0000-0002-5488-2999

Mahan Salehi (M)

Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
ORCID: 0000-0002-4064-4762

Yusif Shakanti (Y)

Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.

Mikael Ekholm (M)

Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.

Matthew Denniff (M)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

Alicja Nazgiewicz (A)

Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.

Felix Eichinger (F)

Department of Medicine, University of Michigan, Ann Arbor, MI, USA.

Bradley Godfrey (B)

Department of Urology and Uro-oncology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.

Andrzej Antczak (A)

Department of Urology and Uro-oncology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.

Maciej Glyda (M)

Department of Transplantology and General Surgery Poznan, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.

Robert Król (R)

Department of General, Vascular and Transplant Surgery, Medical University of Silesia, Katowice, Poland.

Stephen Eyre (S)

Division of Musculoskeletal and Dermatological Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
ORCID: 0000-0002-1251-6974

Jason Brown (J)

Division of Research and Innovation, Manchester University NHS Foundation Trust, Manchester, UK.

Carlo Berzuini (C)

Centre for Biostatistics, School of Health Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
ORCID: 0000-0001-6056-0489

John Bowes (J)

Division of Musculoskeletal and Dermatological Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
ORCID: 0000-0003-4659-031X

Mark Caulfield (M)

William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
National Institute for Health Research, Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, UK.
ORCID: 0000-0001-9295-3594

Ewa Zukowska-Szczechowska (E)

Department of Health Care, Silesian Medical College, Katowice, Poland.

Joanna Zywiec (J)

Department of Internal Medicine, Diabetology and Nephrology, Zabrze, Medical University of Silesia, Katowice, Poland.

Pawel Bogdanski (P)

Department of Obesity, Metabolic Disorders Treatment and Clinical Dietetics, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.

Matthias Kretzler (M)

Department of Medicine, University of Michigan, Ann Arbor, MI, USA.

Adrian S Woolf (AS)

Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Royal Manchester Children's Hospital and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
ORCID: 0000-0001-5541-1358

David Talavera (D)

Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
ORCID: 0000-0002-8820-3931

Bernard Keavney (B)

Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
Division of Cardiology and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
ORCID: 0000-0001-9573-0812

Pasquale Maffia (P)

Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Department of Pharmacy, University of Naples Federico II, Naples, Italy.
ORCID: 0000-0003-3926-4225

Tomasz J Guzik (TJ)

Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Department of Internal and Agricultural Medicine, Jagiellonian University College of Medicine, Kraków, Poland.
ORCID: 0000-0002-5039-7849

Raymond T O'Keefe (RT)

Division of Evolution and Genomic Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
ORCID: 0000-0001-8764-1289

Gosia Trynka (G)

Department of Human Genetics, Wellcome Sanger Institute, Cambridge, UK.
Open Targets, Wellcome Genome Campus, Cambridge, UK.
ORCID: 0000-0002-6955-9529

Nilesh J Samani (NJ)

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
National Institute for Health Research, Leicester Biomedical Research Centre, Leicester, UK.

Aroon Hingorani (A)

Institute of Cardiovascular Science, University College London, London, UK.
ORCID: 0000-0001-8365-0081

Matthew G Sampson (MG)

Division of Nephrology, Boston Children's Hospital, Boston, MA, USA.
The Broad Institute, Cambridge, MA, USA.
Harvard Medical School, Boston, MA, USA.
ORCID: 0000-0001-9560-076X

Andrew P Morris (AP)

Division of Musculoskeletal and Dermatological Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
Department of Biostatistics, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.

Fadi J Charchar (FJ)

Health Innovation and Transformation Centre, School of Science, Psychology and Sport, Federation University Australia, Ballarat, Victoria, Australia.
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
ORCID: 0000-0002-6164-9941

Maciej Tomaszewski (M)

Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK. maciej.tomaszewski@manchester.ac.uk.
Manchester Heart Centre and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK. maciej.tomaszewski@manchester.ac.uk.
ORCID: 0000-0001-8215-6567

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Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Maturation post-transcriptionnelle des ARN › Épissage des ARN › Épissage alternatif › Uncovering genetic mechanisms of hypertension...
questionsmedicales.fr › Phénomènes physiologiques respiratoires et circulatoires › Phénomènes physiologiques cardiovasculaires › Hémodynamique › Pression sanguine › Uncovering genetic mechanisms of hypertension...
questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › Uncovering genetic mechanisms of hypertension...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Uncovering genetic mechanisms of hypertension...
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questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Épidémiologie moléculaire › Étude d'association pangénomique › Uncovering genetic mechanisms of hypertension...
questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Génétique › Génomique › Uncovering genetic mechanisms of hypertension...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Uncovering genetic mechanisms of hypertension...
questionsmedicales.fr › Maladies cardiovasculaires › Maladies vasculaires › Hypertension artérielle › Uncovering genetic mechanisms of hypertension...
questionsmedicales.fr › Appareil urogénital › Voies urinaires › Rein › Uncovering genetic mechanisms of hypertension...
questionsmedicales.fr › Techniques d'investigation › Analyse de randomisation mendélienne › Uncovering genetic mechanisms of hypertension...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Polymorphisme génétique › Polymorphisme de nucléotide simple › Uncovering genetic mechanisms of hypertension...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Locus génétiques › Locus de caractère quantitatif › Uncovering genetic mechanisms of hypertension...