Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

  • Praveen Surendran
  • Elena V Feofanova
  • Najim Lahrouchi
  • Ioanna Ntalla
  • Savita Karthikeyan
  • James Cook
  • Lingyan Chen
  • Borbala Mifsud
  • Chen Yao
  • Aldi T Kraja
  • James H Cartwright
  • Jacklyn N Hellwege
  • Ayush Giri
  • Vinicius Tragante
  • Gudmar Thorleifsson
  • Dajiang J Liu
  • Bram P Prins
  • Isobel D Stewart
  • Claudia P Cabrera
  • James M Eales
  • Artur Akbarov
  • Paul L Auer
  • Lawrence F Bielak
  • Joshua C Bis
  • Vickie S Braithwaite
  • Jennifer A Brody
  • E Warwick Daw
  • Helen R Warren
  • Fotios Drenos
  • Sune Fallgaard Nielsen
  • Jessica D Faul
  • Eric B Fauman
  • Cristiano Fava
  • Teresa Ferreira
  • Christopher N Foley
  • Nora Franceschini
  • He Gao
  • Olga Giannakopoulou
  • Franco Giulianini
  • Daniel F Gudbjartsson
  • Xiuqing Guo
  • Sarah E Harris
  • Aki S Havulinna
  • Anna Helgadottir
  • Jennifer E Huffman
  • Shih-Jen Hwang
  • Stavroula Kanoni
  • Jukka Kontto
  • Martin G Larson
  • Ruifang Li-Gao
  • Jaana Lindström
  • Luca A Lotta
  • Yingchang Lu
  • Jian'an Luan
  • Anubha Mahajan
  • Giovanni Malerba
  • Nicholas G D Masca
  • Hao Mei
  • Cristina Menni
  • Dennis O Mook-Kanamori
  • David Mosen-Ansorena
  • Martina Müller-Nurasyid
  • Guillaume Paré
  • Dirk S Paul
  • Markus Perola
  • Alaitz Poveda
  • Rainer Rauramaa
  • Melissa Richard
  • Tom G Richardson
  • Nuno Sepúlveda
  • Xueling Sim
  • Albert V Smith
  • Jennifer A Smith
  • James R Staley
  • Alena Stanáková
  • Patrick Sulem
  • Sébastien Thériault
  • Unnur Thorsteinsdottir
  • Stella Trompet
  • Tibor V Varga
  • Digna R Velez Edwards
  • Giovanni Veronesi
  • Stefan Weiss
  • Sara M Willems
  • Jie Yao
  • Robin Young
  • Bing Yu
  • Weihua Zhang
  • Jing-Hua Zhao
  • Wei Zhao
  • Wei Zhao
  • Evangelos Evangelou
  • Stefanie Aeschbacher
  • Eralda Asllanaj
  • Stefan Blankenberg
  • Lori L Bonnycastle
  • Jette Bork-Jensen
  • Ivan Brandslund
  • Peter S Braund
  • Stephen Burgess
  • Kelly Cho
  • Cramer Christensen
  • John Connell
  • Renée de Mutsert
  • Anna F Dominiczak
  • Marcus Dörr
  • Gudny Eiriksdottir
  • Aliki-Eleni Farmaki
  • J Michael Gaziano
  • Niels Grarup
  • Megan L Grove
  • Göran Hallmans
  • Torben Hansen
  • Christian T Have
  • Gerardo Heiss
  • Marit E Jørgensen
  • Pekka Jousilahti
  • Eero Kajantie
  • Mihir Kamat
  • AnneMari Käräjämäki
  • Fredrik Karpe
  • Heikki A Koistinen
  • Csaba P Kovesdy
  • Kari Kuulasmaa
  • Tiina Laatikainen
  • Lars Lannfelt
  • I-Te Lee
  • Wen-Jane Lee
  • Allan Linneberg
  • Lisa W Martin
  • Marie Moitry
  • Girish Nadkarni
  • Matt J Neville
  • Colin N A Palmer
  • George J Papanicolaou
  • Oluf Pedersen
  • James Peters
  • Neil Poulter
  • Asif Rasheed
  • Katrine L Rasmussen
  • N William Rayner
  • Reedik Mägi
  • Frida Renström
  • Rainer Rettig
  • Jacques Rossouw
  • Pamela J Schreiner
  • Peter S Sever
  • Emil L Sigurdsson
  • Tea Skaaby
  • Yan V Sun
  • Johan Sundstrom
  • Gudmundur Thorgeirsson
  • Tõnu Esko
  • Elisabetta Trabetti
  • Philip S Tsao
  • Tiinamaija Tuomi
  • Stephen T Turner
  • Ioanna Tzoulaki
  • Ilonca Vaartjes
  • Anne-Claire Vergnaud
  • Cristen J Willer
  • Peter W F Wilson
  • Daniel R Witte
  • Ekaterina Yonova-Doing
  • He Zhang
  • Naheed Aliya
  • Peter Almgren
  • Philippe Amouyel
  • Folkert W Asselbergs
  • Michael R Barnes
  • Alexandra I Blakemore
  • Michael Boehnke
  • Michiel L Bots
  • Erwin P Bottinger
  • Julie E Buring
  • John C Chambers
  • Yii-Der Ida Chen
  • Rajiv Chowdhury
  • David Conen
  • Adolfo Correa
  • George Davey Smith
  • Rudolf A de Boer
  • Ian J Deary
  • George Dedoussis
  • Panos Deloukas
  • Emanuele Di Angelantonio
  • Paul Elliott
  • Stephan B Felix
  • Jean Ferrières
  • Ian Ford
  • Myriam Fornage
  • Paul W Franks
  • Stephen Franks
  • Philippe Frossard
  • Giovanni Gambaro
  • Tom R Gaunt
  • Leif Groop
  • Vilmundur Gudnason
  • Tamara B Harris
  • Caroline Hayward
  • Branwen J Hennig
  • Karl-Heinz Herzig
  • Erik Ingelsson
  • Jaakko Tuomilehto
  • Marjo-Riitta Järvelin
  • J Wouter Jukema
  • Sharon L R Kardia
  • Frank Kee
  • Jaspal S Kooner
  • Charles Kooperberg
  • Lenore J Launer
  • Lars Lind
  • Ruth J F Loos
  • Abdulla Al Shafi Majumder
  • Markku Laakso
  • Mark I McCarthy
  • Olle Melander
  • Karen L Mohlke
  • Alison D Murray
  • Børge Grønne Nordestgaard
  • Marju Orho-Melander
  • Chris J Packard
  • Sandosh Padmanabhan
  • Walter Palmas
  • Ozren Polasek
  • David J Porteous
  • Andrew M Prentice
  • Michael A Province
  • Caroline L Relton
  • Kenneth Rice
  • Paul M Ridker
  • Olov Rolandsson
  • Frits R Rosendaal
  • Jerome I Rotter
  • Igor Rudan
  • Veikko Salomaa
  • Nilesh J Samani
  • Naveed Sattar
  • Wayne H-H Sheu
  • Blair H Smith
  • Nicole Soranzo
  • Timothy D Spector
  • John M Starr
  • Sylvain Sebert
  • Kent D Taylor
  • Timo A Lakka
  • Nicholas J Timpson
  • Martin D Tobin
  • Pim van der Harst
  • Peter van der Meer
  • Vasan S Ramachandran
  • Niek Verweij
  • Jarmo Virtamo
  • Uwe Völker
  • David R Weir
  • Eleftheria Zeggini
  • Fadi J Charchar
  • Nicholas J Wareham
  • Claudia Langenberg
  • Maciej Tomaszewski
  • Adam S Butterworth
  • Mark J Caulfield
  • John Danesh
  • Todd L Edwards
  • Hilma Holm
  • Adriana M Hung
  • Cecilia M Lindgren
  • Chunyu Liu
  • Alisa K Manning
  • Andrew P Morris
  • Alanna C Morrison
  • Christopher J O'Donnell
  • Bruce M Psaty
  • Danish Saleheen
  • Kari Stefansson
  • Eric Boerwinkle
  • Daniel I Chasman
  • Daniel Levy
  • Christopher Newton-Cheh
  • Patricia B Munroe
  • Joanna M M Howson
  • LifeLines Cohort Study

Abstract

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10-8), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.

Bibliografische Daten

OriginalspracheEnglisch
ISSN1061-4036
DOIs
StatusVeröffentlicht - 12.2020
PubMed 33230300