Discovery of novel heart rate-associated loci using the Exome Chip

Marten E van den Berg; Helen R Warren; Claudia P Cabrera; Niek Verweij; Borbala Mifsud; Jeffrey Haessler; Nathan A Bihlmeyer; Yi-Ping Fu; Stefan Weiss; Henry J Lin; Niels Grarup; Ruifang Li-Gao; Giorgio Pistis; Nabi Shah; Jennifer A Brody; Martina Müller-Nurasyid; Honghuang Lin; Hao Mei; Albert V Smith; Leo-Pekka Lyytikäinen; Leanne M Hall; Jessica van Setten; Stella Trompet; Bram P Prins; Aaron Isaacs; Farid Radmanesh; Jonathan Marten; Aiman Entwistle; Jan A Kors; Claudia T Silva; Alvaro Alonso; Joshua C Bis; Rudolf de Boer; Hugoline G de Haan; Renée de Mutsert; George Dedoussis; Anna F Dominiczak; Alex S F Doney; Patrick T Ellinor; Ruben N Eppinga; Stephan B Felix; Xiuqing Guo; Yanick Hagemeijer; Torben Hansen; Tamara B Harris; Susan R Heckbert; Paul L Huang; Shih-Jen Hwang; Mika Kähönen; Jørgen K Kanters; Ivana Kolcic; Lenore J Launer; Man Li; Jie Yao; Allan Linneberg; Simin Liu; Peter W Macfarlane; Massimo Mangino; Andrew D Morris; Antonella Mulas; Alison D Murray; Christopher P Nelson; Marco Orrú; Sandosh Padmanabhan; Annette Peters; David J Porteous; Neil Poulter; Bruce M Psaty; Lihong Qi; Olli T Raitakari; Fernando Rivadeneira; Carolina Roselli; Igor Rudan; Naveed Sattar; Peter Sever; Moritz F Sinner; Elsayed Z Soliman; Timothy D Spector; Alice V Stanton; Kathleen E Stirrups; Kent D Taylor; Martin D Tobin; André Uitterlinden; Ilonca Vaartjes; Arno W Hoes; Peter van der Meer; Uwe Völker; Melanie Waldenberger; Zhijun Xie; Magdalena Zoledziewska; Andrew Tinker; Ozren Polasek; Jonathan Rosand; Yalda Jamshidi; Cornelia M van Duijn; Eleftheria Zeggini; J Wouter Jukema; Folkert W Asselbergs; Nilesh J Samani; Terho Lehtimäki; Vilmundur Gudnason; James Wilson; Steven A Lubitz; Stefan Kääb; Nona Sotoodehnia; Mark J Caulfield; Colin N A Palmer; Serena Sanna; Dennis O Mook-Kanamori; Panos Deloukas; Oluf Pedersen; Jerome I Rotter; Marcus Dörr; Chris J O'Donnell; Caroline Hayward; Dan E Arking; Charles Kooperberg; Pim van der Harst; Mark Eijgelsheim; Bruno H Stricker; Patricia B Munroe

doi:10.1093/hmg/ddx113

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Discovery of novel heart rate-associated loci using the Exome Chip

Journal article

Open access

Peer reviewed

Discovery of novel heart rate-associated loci using the Exome Chip

Marten E van den Berg, Helen R Warren, Claudia P Cabrera, Niek Verweij, Borbala Mifsud, Jeffrey Haessler, Nathan A Bihlmeyer, Yi-Ping Fu, Stefan Weiss, Henry J Lin, …

Human molecular genetics, Vol.26(12), pp.2346-2363

15/06/2017

DOI: https://doi.org/10.1093/hmg/ddx113

PMID: 28379579

Abstract

Adult

Alleles

Exome

Female

Gene Frequency - genetics

Genetic Loci

Genetic Predisposition to Disease

Genome-Wide Association Study - methods

Genotype

Heart Rate - genetics

Heart Rate - physiology

Humans

Male

Middle Aged

Oligonucleotide Array Sequence Analysis

Polymorphism, Single Nucleotide - genetics

Risk Factors

Whites - genetics

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

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Title: Discovery of novel heart rate-associated loci using the Exome Chip
Creators - without role: Marten E van den Berg - Erasmus MC
Helen R Warren - William Harvey Research Institute
Claudia P Cabrera - William Harvey Research Institute
Niek Verweij - University Medical Center Groningen
Borbala Mifsud - William Harvey Research Institute
Jeffrey Haessler - Fred Hutch Cancer Center
Nathan A Bihlmeyer - Johns Hopkins Medicine
Yi-Ping Fu - National Heart Lung and Blood Institute
Stefan Weiss - University of Greifswald
Henry J Lin - The Lundquist Institute
Niels Grarup - Novo Nordisk Foundation
Ruifang Li-Gao - Leiden University Medical Center
Giorgio Pistis - Institute of Genetic and Biomedical Research
Nabi Shah - University of Dundee
Jennifer A Brody - University of Washington
Martina Müller-Nurasyid - Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-Universität, Munich, Germany
Honghuang Lin - Boston University
Hao Mei - Jackson Memorial Hospital
Albert V Smith - University of Iceland
Leo-Pekka Lyytikäinen - Fimlab
Leanne M Hall - NIHR Leicester Cardiovascular Biomedical Research Unit
Jessica van Setten - University Medical Center Utrecht
Stella Trompet - Leiden University Medical Center
Bram P Prins - Wellcome Sanger Institute
Aaron Isaacs - Maastricht University
Farid Radmanesh - Broad Institute
Jonathan Marten - MRC Institute of Genetics and Molecular Medicine
Aiman Entwistle - William Harvey Research Institute
Jan A Kors - Erasmus MC
Claudia T Silva - Universidad del Rosario
Alvaro Alonso - Emory University
Joshua C Bis - University of Washington
Rudolf de Boer - University Medical Center Groningen
Hugoline G de Haan - Leiden University Medical Center
Renée de Mutsert - Leiden University Medical Center
George Dedoussis - Harokopio University of Athens
Anna F Dominiczak - University of Glasgow
Alex S F Doney - University of Dundee
Patrick T Ellinor - Broad Institute
Ruben N Eppinga - University Medical Center Groningen
Stephan B Felix - Greifswald University Hospital
Xiuqing Guo - The Lundquist Institute
Yanick Hagemeijer - University Medical Center Groningen
Torben Hansen - University of Copenhagen
Tamara B Harris - National Institute on Aging
Susan R Heckbert - University of Washington
Paul L Huang - Massachusetts General Hospital
Shih-Jen Hwang - Office of Extramural Research
Mika Kähönen - FinnMedi
Jørgen K Kanters - University of Copenhagen
Ivana Kolcic - University of Split
Lenore J Launer - National Institutes of Health
Man Li - University of Utah
Jie Yao - The Lundquist Institute
Allan Linneberg - Capital Region of Denmark
Simin Liu - Brown University
Peter W Macfarlane - University of Glasgow
Massimo Mangino - King's College London
Andrew D Morris - University of Edinburgh
Antonella Mulas - Institute of Genetic and Biomedical Research
Alison D Murray - University of Aberdeen
Christopher P Nelson - NIHR Leicester Cardiovascular Biomedical Research Unit
Marco Orrú - Azienda Ospedaliera G. Brotzu
Sandosh Padmanabhan - University of Glasgow
Annette Peters - German Centre for Cardiovascular Research
David J Porteous - Western General Hospital
Neil Poulter - Imperial College London
Bruce M Psaty - University of Washington
Lihong Qi - University of California, Davis
Olli T Raitakari - Turku University Hospital
Fernando Rivadeneira - Erasmus MC
Carolina Roselli - Broad Institute
Igor Rudan - University of Edinburgh
Naveed Sattar - University of Glasgow
Peter Sever - Imperial College London
Moritz F Sinner - German Centre for Cardiovascular Research
Elsayed Z Soliman - Wake Forest University
Timothy D Spector - King's College London
Alice V Stanton - Royal College of Surgeons in Ireland
Kathleen E Stirrups - Queen Mary University of London
Kent D Taylor - The Lundquist Institute
Martin D Tobin - University of Leicester
André Uitterlinden - Erasmus MC
Ilonca Vaartjes - University Medical Center
Arno W Hoes - Helmholtz Zentrum München
Peter van der Meer - University Medical Center Groningen
Uwe Völker - University of Greifswald
Melanie Waldenberger - Helmholtz Zentrum München
Zhijun Xie - Boston University
Magdalena Zoledziewska - Institute of Genetic and Biomedical Research
Andrew Tinker - William Harvey Research Institute
Ozren Polasek - University of Split
Jonathan Rosand - Center for Human Genetics
Yalda Jamshidi - St George's, University of London
Cornelia M van Duijn - University Hospital and Clinics
Eleftheria Zeggini - Wellcome Sanger Institute
J Wouter Jukema - Leiden University Medical Center
Folkert W Asselbergs - University Medical Center Utrecht
Nilesh J Samani - University of Leicester
Terho Lehtimäki - Fimlab
Vilmundur Gudnason - University of Iceland
James Wilson - University of Mississippi Medical Center
Steven A Lubitz - Massachusetts General Hospital
Stefan Kääb - Department of Medicine I, University Hospital Munich, Ludwig-Maximilians-Universität, Munich, Germany
Nona Sotoodehnia - University of Washington
Mark J Caulfield - Queen Mary University of London
Colin N A Palmer - University of Dundee
Serena Sanna - GeneTiCA
Dennis O Mook-Kanamori - Leiden University Medical Center
Panos Deloukas - Queen Mary University of London
Oluf Pedersen - University of Copenhagen
Jerome I Rotter - The Lundquist Institute
Marcus Dörr
Chris J O'Donnell - Boston Veteran's Administration Healthcare, Boston MA, USA
Caroline Hayward - University of Edinburgh
Dan E Arking - Johns Hopkins University School of Medicine
Charles Kooperberg - Hutchinson
Pim van der Harst - University Medical Center Groningen
Mark Eijgelsheim - Department of Epidemiology Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, 3000CA, Rotterdam, the Netherlands
Bruno H Stricker - Department of Epidemiology Erasmus MC - University Medical Center Rotterdam, P.O. Box 2040, 3000CA, Rotterdam, the Netherlands
Patricia B Munroe - Queen Mary University of London
Publication Details: Human molecular genetics, Vol.26(12), pp.2346-2363
Grant note: K23 NS059774 / NINDS NIH HHS N01HC95169 / NHLBI NIH HHS HHSN268201600003C / NHLBI NIH HHS RC2 HG005581 / NHGRI NIH HHS R01 HG007089 / NHGRI NIH HHS HHSN268201000031C / NHLBI NIH HHS R01 NS073344 / NINDS NIH HHS MC_QA137853 / Medical Research Council R01 HL071251 / NHLBI NIH HHS N01HC95163 / NHLBI NIH HHS N01HC95166 / NHLBI NIH HHS R01 HL103612 / NHLBI NIH HHS R01 HL117626 / NHLBI NIH HHS HHSN268201100010C / NHLBI NIH HHS HHSN268201100005C / NHLBI NIH HHS HHSN268201500001I / NHLBI NIH HHS HHSN268201500003C / NHLBI NIH HHS MR/N01104X/1 / Medical Research Council HHSN268201300049C / NHLBI NIH HHS MR/L016311/1 / Medical Research Council HHSN268201100005I / NHLBI NIH HHS UL1 RR033176 / NCRR NIH HHS MC_PC_U127561128 / Medical Research Council R01 HL092577 / NHLBI NIH HHS UL1 TR000040 / NCATS NIH HHS P30 DK063491 / NIDDK NIH HHS R01 HL087652 / NHLBI NIH HHS MC_PC_14089 / Medical Research Council Wellcome Trust U01 HL080295 / NHLBI NIH HHS R01 HL120393 / NHLBI NIH HHS N01HC95161 / NHLBI NIH HHS R01 HL071250 / NHLBI NIH HHS N01HC85083 / NHLBI NIH HHS K23 HL114724 / NHLBI NIH HHS HHSN268201100012C / NHLBI NIH HHS R01 HL111089 / NHLBI NIH HHS U01 HL117626 / NHLBI NIH HHS R01 AG023629 / NIA NIH HHS HHSN268201300047C / NHLBI NIH HHS PG/12/38/29615 / British Heart Foundation HHSN268201600002C / NHLBI NIH HHS UL1 TR001079 / NCATS NIH HHS HHSN268201200036C / NHLBI NIH HHS U01 HL130114 / NHLBI NIH HHS N01HC85082 / NHLBI NIH HHS HHSN268201300046C / NHLBI NIH HHS N01HC95160 / NHLBI NIH HHS G0600237 / Medical Research Council MR/M501633/1 / Medical Research Council G1001799 / Medical Research Council PG/17/59/33139 / British Heart Foundation HHSN268201600004C / NHLBI NIH HHS MR/N005813/1 / Medical Research Council MC_PC_13040 / Medical Research Council N01HC85079 / NHLBI NIH HHS HHSN268201100007C / NHLBI NIH HHS UL1 TR001881 / NCATS NIH HHS R01 HG007022 / NHGRI NIH HHS HHSN268201100005G / NHLBI NIH HHS MR/N01104X/2 / Medical Research Council HHSN268201100011C / NHLBI NIH HHS HHSN268201100011I / NHLBI NIH HHS HHSN268201100007I / NHLBI NIH HHS UL1 RR025005 / NCRR NIH HHS HHSN268201600001C / NHLBI NIH HHS R01 HL071252 / NHLBI NIH HHS MR/K006584/1 / Medical Research Council G0000934 / Medical Research Council N01HC25195 / NHLBI NIH HHS N01HC85081 / NHLBI NIH HHS N01HC95168 / NHLBI NIH HHS R01 HL071258 / NHLBI NIH HHS N01HC95165 / NHLBI NIH HHS N01HC95162 / NHLBI NIH HHS N01HC85086 / NHLBI NIH HHS 068545/Z/02 / Wellcome Trust N01HC95164 / NHLBI NIH HHS HHSN268201500001C / NHLBI NIH HHS HHSN268201100008I / NHLBI NIH HHS N01HC85080 / NHLBI NIH HHS N01HC95159 / NHLBI NIH HHS U01 HG006513 / NHGRI NIH HHS HHSN268201100006C / NHLBI NIH HHS HHSN271201100005C / NIDA NIH HHS UL1 TR000124 / NCATS NIH HHS K24 HL105780 / NHLBI NIH HHS G9521010 / Medical Research Council RC2 HL102419 / NHLBI NIH HHS HHSN268200800007C / NHLBI NIH HHS N01HC55222 / NHLBI NIH HHS S10 OD020069 / NIH HHS HHSN268201100008C / NHLBI NIH HHS MR/M501633/2 / Medical Research Council RC2 HG005552 / NHGRI NIH HHS MR/K007017/1 / Medical Research Council R01 HL105756 / NHLBI NIH HHS R01 HL071259 / NHLBI NIH HHS R01 HL116747 / NHLBI NIH HHS HHSN268201300050C / NHLBI NIH HHS R01 NS059727 / NINDS NIH HHS R01 HL071205 / NHLBI NIH HHS HHSN268201100009C / NHLBI NIH HHS MR/N025083/1 / Medical Research Council RG/14/5/30893 / British Heart Foundation HHSN268201100009I / NHLBI NIH HHS
Identifiers: 9934732008331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article