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

2019-11-22T16:16:04Z (GMT) by 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 NA 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

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.