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

van den Berg, M. E. et al. (2017) Discovery of novel heart rate-associated loci using the Exome Chip. Human Molecular Genetics, 26(12), pp. 2346-2363. (doi:10.1093/hmg/ddx113) (PMID:28379579) (PMCID:PMC5458336)

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Abstract

Background: Resting heart rate is a heritable trait, that when abnormal is associated with increased mortality risk. GWAS analyses have found loci associated with resting heart rate, but these loci explain only a small fraction of the variation. Aim: To discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Methods: 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 = 135,000). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods. Results We discovered five novel heart rate loci, and one new independent low-frequency missense variant in a established heart rate locus (KIAA1755). Lead variants in four of the novel loci are missense variants in the genes C10orf71, DALDR3, TESK2, 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, 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. Conclusion: Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Macfarlane, Professor Peter and Padmanabhan, Professor Sandosh and Dominiczak, Professor Anna and Sattar, Professor Naveed
Authors: van den Berg, M. E., Warren, H. R., Cabrera, C. P., Verweij, N., Mifsud, B., Harssler, J., Bihlmeyer, N. A., Fu, Y.-P., 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., 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.-J., 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., Orrú, M., Padmanabhan, S., Peters, A., Porteous, D. J., Poulter, N., Pstay, 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., Völker, 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., Lubitz, S. A., Kääb, S., Sotoodehnia, N., Caulfield, M. J., Palmer, C. N.A., Sanna, S., Mook-Kanamori, D. O., Deloukas, P., Pedersen, O., Rotter, J. I., Dörr, M., O'Donnell, C. J., Hayward, C., Arking, D. E., Kooperberg, C., van der Harst, P., Eijgelsheim, M., Stricker, B. H., and Munroe, P. B.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Robertson Centre
Journal Name:Human Molecular Genetics
Publisher:Oxford University Press
ISSN:0964-6906
ISSN (Online):1460-2083
Published Online:03 April 2017
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Human Molecular Genetics 26(12): 2346-2363
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
690421Glasgow Molecular Pathology (GMP) NodeKarin OienMedical Research Council (MRC)MR/N005813/1ICS - EXPERIMENTAL THERAPEUTICS