Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Research output: Contribution to journalArticle

Abstract

High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used -1/4155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.

Details

Authors
  • Praveen Surendran
  • Fotios Drenos
  • Robin Young
  • Helen Warren
  • James P. Cook
  • Alisa K. Manning
  • Niels Grarup
  • Xueling Sim
  • Daniel R. Barnes
  • Kate Witkowska
  • James R. Staley
  • Vinicius Tragante
  • Taru Tukiainen
  • Hanieh Yaghootkar
  • Nicholas Masca
  • Daniel F. Freitag
  • Teresa Ferreira
  • Olga Giannakopoulou
  • Andrew Tinker
  • Magdalena Harakalova
  • Evelin Mihailov
  • Chunyu Liu
  • Aldi T. Kraja
  • Sune Fallgaard Nielsen
  • Asif Rasheed
  • Maria Samuel
  • Wei Zhao
  • Lori L. Bonnycastle
  • Anne U. Jackson
  • Narisu Narisu
  • Amy J. Swift
  • Lorraine Southam
  • Jonathan Marten
  • Jeroen R. Huyghe
  • Alena Stančáková
  • Angela Matchan
  • Kathleen E. Stirrups
  • Jette Bork-Jensen
  • Anette P. Gjesing
  • Jukka Kontto
  • Markus Perola
  • Susan Shaw-Hawkins
  • Aki S. Havulinna
  • He Zhang
  • Louise A. Donnelly
  • Christopher J. Groves
  • N. William Rayner
  • Matt J. Neville
  • Neil R. Robertson
  • Andrianos M. Yiorkas
  • Karl Heinz Herzig
  • Eero Kajantie
  • Weihua Zhang
  • Sara M. Willems
  • Lars Lannfelt
  • Giovanni Malerba
  • Nicole Soranzo
  • Elisabetta Trabetti
  • Niek Verweij
  • Evangelos Evangelou
  • Alireza Moayyeri
  • Anne Claire Vergnaud
  • Christopher P. Nelson
  • Muriel Caslake
  • Anton J M De Craen
  • Stella Trompet
  • Jian'An Luan
  • Robert A. Scott
  • Sarah E. Harris
  • David C M Liewald
  • Riccardo Marioni
  • Cristina Menni
  • Aliki Eleni Farmaki
  • Göran Hallmans
  • Jennifer E. Huffman
  • Maija Hassinen
  • Stephen Burgess
  • Ramachandran S. Vasan
  • Janine F. Felix
  • Maria Uria-Nickelsen
  • Anders Malarstig
  • Dermot F. Reilly
  • Maarten Hoek
  • Thomas F. Vogt
  • Honghuang Lin
  • Wolfgang Lieb
  • Matthew Traylor
  • Hugh S. Markus
  • Heather M. Highland
  • Anne E. Justice
  • Eirini Marouli
  • Jaana Lindström
  • Matti Uusitupa
  • Pirjo Komulainen
  • Timo A. Lakka
  • Rainer Rauramaa
  • Ozren Polasek
  • Igor Rudan
  • Olov Rolandsson
  • George Dedoussis
  • Timothy D. Spector
  • Pekka Jousilahti
  • Satu Männistö
  • Ian J. Deary
  • John M. Starr
  • Claudia Langenberg
  • Nick J. Wareham
  • Morris J. Brown
  • Anna F. Dominiczak
  • John M. Connell
  • J. Wouter Jukema
  • Naveed Sattar
  • Ian Ford
  • Chris J. Packard
  • Tõnu Esko
  • Reedik Mägi
  • Andres Metspalu
  • Rudolf A. De Boer
  • Peter Van Der Meer
  • Pim Van Der Harst
  • Giovanni Gambaro
  • Erik Ingelsson
  • Lars Lind
  • Paul I W De Bakker
  • Mattijs E. Numans
  • Ivan Brandslund
  • Cramer Christensen
  • Eva R B Petersen
  • Eeva Korpi-Hyövälti
  • Heikki Oksa
  • John C. Chambers
  • Jaspal S. Kooner
  • Alexandra I F Blakemore
  • Steve Franks
  • Marjo Riitta Jarvelin
  • Lise L. Husemoen
  • Allan Linneberg
  • Tea Skaaby
  • Betina Thuesen
  • Fredrik Karpe
  • Jaakko Tuomilehto
  • Alex S F Doney
  • Andrew D. Morris
  • Colin N A Palmer
  • Oddgeir Lingaas Holmen
  • Kristian Hveem
  • Cristen J. Willer
  • Tiinamaija Tuomi
  • Annemari Käräjämäki
  • Aarno Palotie
  • Samuli Ripatti
  • Veikko Salomaa
  • Dewan S. Alam
  • Abdulla Al Shafi Majumder
  • Emanuele Di Angelantonio
  • Rajiv Chowdhury
  • Mark I. McCarthy
  • Neil Poulter
  • Alice V. Stanton
  • Peter Sever
  • Philippe Amouyel
  • Dominique Arveiler
  • Stefan Blankenberg
  • Jean Ferrières
  • Frank Kee
  • Kari Kuulasmaa
  • Martina Müller-Nurasyid
  • Giovanni Veronesi
  • Jarmo Virtamo
  • Panos Deloukas
  • Paul Elliott
  • Eleftheria Zeggini
  • Sekar Kathiresan
  • Johanna Kuusisto
  • Markku Laakso
  • Sandosh Padmanabhan
  • David J. Porteous
  • Caroline Hayward
  • Generation Scotland
  • Francis S. Collins
  • Karen L. Mohlke
  • Torben Hansen
  • Oluf Pedersen
  • Michael Boehnke
  • Heather M. Stringham
  • Philippe Frossard
  • Christopher Newton-Cheh
  • Martin D. Tobin
  • Børge Grønne Nordestgaard
  • Mark J. Caulfield
  • Anubha Mahajan
  • Andrew P. Morris
  • Maciej Tomaszewski
  • Nilesh J. Samani
  • Danish Saleheen
  • Folkert W. Asselbergs
  • Cecilia M. Lindgren
  • John Danesh
  • Louise V. Wain
  • Adam S. Butterworth
  • Joanna M M Howson
  • Patricia B. Munroe
Organisations
External organisations
  • University of Liverpool
  • Massachusetts General Hospital
  • University Medical Center Utrecht
  • University of Exeter
  • National Institute for Health Research, United Kingdom
  • Queen Mary University
  • Centre for Non-Communicable Diseases
  • University of Pennsylvania
  • National Human Genome Research Institute
  • Wellcome Trust Sanger Institute
  • University of Edinburgh
  • University of Eastern Finland
  • University of Verona
  • National Institute for Health and Welfare
  • University of Helsinki
  • University of Oxford
  • Brunel University London
  • Poznan University of Medical Sciences
  • Ealing Hospital
  • Uppsala University
  • University of Ioannina
  • University of the Basque Country
  • University of Glasgow
  • Leiden University Medical Centre
  • University of Queensland
  • King's College London
  • Harokopio University
  • Umeå University
  • Boston University
  • Erasmus University Medical Center
  • Pfizer
  • Merck Research Laboratories
  • University of Kiel
  • University of North Carolina
  • Kuopio University Hospital
  • University of Split
  • Harvard University
  • Interuniversity Cardiology Institute of the Netherlands
  • Boston Children's Hospital
  • University of Tartu
  • University of Groningen
  • University of Southern Denmark
  • Lillebaelt Hospital
  • South Ostrobothnia Central Hospital
  • Tampere University Hospital
  • Barts Health NHS Trust
  • Imperial College London
  • Research Centre for Prevention and Health
  • King Abdulaziz University
  • St. Olav’s University Hospital
  • Nord-Trøndelag Health Trust
  • University of Michigan
  • Folkhälsan Research Centre
  • Helsinki University Central Hospital
  • Vaasa Central Hospital
  • Broad Institute
  • International Centre for Diarrhoeal Disease Research, Bangladesh
  • National Institute of Cardiovascular Diseases
  • Royal College of Surgeons in Ireland
  • Pasteur Institute of Lille
  • University of Strasbourg
  • University Medical Center Hamburg-Eppendorf
  • University of Toulouse
  • Queen's University Belfast
  • German Centre for Cardiovascular Research
  • University of Insubria
  • University of Leicester
  • University of Manchester
  • University of Cambridge
  • University of Bristol
  • University College London
  • University of Copenhagen
  • National University of Singapore
  • National Heart Lung and Blood Institute
  • Washington University in St. Louis
  • Copenhagen University Hospital
  • University of Dundee
  • University of Oulu
  • Catholic University of the Sacred Heart
  • Stanford University
  • Ninewells Hospital and Medical School
  • Oulu University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Cardiac and Cardiovascular Systems
Original languageEnglish
Pages (from-to)1151-1161
Number of pages11
JournalNature Genetics
Volume48
Issue number10
StatePublished - 2016 Oct 1
Publication categoryResearch
Peer-reviewedYes