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van den Berg, M.* ; Warren, H.R.* ; Cabrera, C.P.* ; Verweij, N.* ; Mifsud, B.* ; Haessler, J.* ; Bihlmeyer, N.A.* ; Fu, Y.* ; Weiss, S.* ; Lin, H.J.* ; Grarup, N.* ; Li-Gao, R.* ; Pistis, G.* ; Shah, N.* ; Brody, J.A.* ; Müller-Nurasyid, M. ; Lin, H.* ; Mei, H.* ; Smith, A.V.* ; Lyytikäinen, L.-P.* ; Hall, L.M.* ; van Setten, J.* ; Trompet, S.* ; Prins, B.P.* ; Isaacs, A.* ; Radmanesh, F.* ; Marten, J.* ; Entwistle, A.* ; Kors, J.A.* ; Silva, C.T.* ; Alonso, A.* ; Bis, J.C.* ; de Boer, R.A.* ; de Haan, H.G.* ; de Mutsert, R.* ; Dedoussis, G.* ; Dominiczak, A.F.* ; Doney, A.S.F.* ; Ellinor, P.T.* ; Eppinga, R.N.* ; Felix, S.B.* ; Guo, X.* ; Hagemeijer, Y.* ; Hansen, T.* ; Harris, T.B.* ; Heckbert, S.R.* ; Huang, P.L.* ; Hwang, S.H.* ; Kähönen, M.* ; Kanters, J.K.* ; Kolcic, I.* ; Launer, L.J.* ; Li, M.* ; Yao, J.* ; Linneberg, A.* ; Liu, S.* ; Macfarlane, P.W.* ; Mangino, M.* ; Morris, A.D.* ; Mulas, A.* ; Murray, A.D.* ; Nelson, C.P.* ; Orrù, M.* ; Padmanabhan, S.* ; Peters, A. ; Porteous, D.J.* ; Poulter, N.* ; Psaty, B.M.* ; Qi, L.* ; Raitakari, O.T.* ; Rivadeneira, F.* ; Roselli, C.* ; Rudan, I.* ; Sattar, N.* ; Sever, P.* ; Sinner, M.F.* ; Soliman, E.Z.* ; Spector, T.D.* ; Stanton, A.V.* ; Stirrups, K.E.* ; Taylor, K.D.* ; Tobin, M.D.* ; Uitterlinden, A.* ; Vaartjes, I.* ; Hoes, A.W. ; van der Meer, P.* ; Voelker, U.* ; Waldenberger, M. ; Xie, Z.* ; Zoledziewska, M.* ; Tinker, A.* ; Polasek, O.* ; Rosand, J.* ; Jamshidi, Y.* ; van Duijn, C.M.* ; Zeggini, E.* ; Jukema, J.W.* ; Asselbergs, F.W.* ; Samani, N.J.* ; Lehtimäki, T.* ; Gudnason, V.* ; Wilson, J.B.* ; Lubitz, S.A.* ; Kaeaeb, S.* ; Sotoodehnia, N.* ; Caulfield, M.J.* ; Palmer, C.N.A.* ; Sanna, S.* ; Mook-Kanamori, D.O.* ; Deloukas, P.* ; Pedersen, O.* ; Rotter, J.I.* ; Doerr, M.* ; O'Donnell, C.J.* ; Hayward, C.* ; Arking, D.E.* ; Kooperberg, C.* ; van der Harst, P.* ; Eijgelsheim, M.* ; Stricker, B.H.* ; Munroe, P.B.*

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

Hum. Mol. Genet. 26, 2346-2363 (2017)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Genome-wide Association; All-cause Mortality; Complex Traits; Risk-factor; Identification; Variants; Disease; Project; Protein; Gene
Sprache englisch
Veröffentlichungsjahr 2017
HGF-Berichtsjahr 2017
ISSN (print) / ISBN 0964-6906
e-ISSN 1460-2083
Zeitschrift Human Molecular Genetics
Quellenangaben Band: 26, Heft: 12, Seiten: 2346-2363 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Oxford
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Genetic Epidemiology (IGE)
Institute of Epidemiology (EPI)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30202 - Environmental Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-504100-001
G-504000-001
G-504091-001
PubMed ID 28379579
DOI 10.1093/hmg/ddx113
WOS ID WOS:000402819800014
Scopus ID 85031038119
Erfassungsdatum 2017-07-03
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