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

Authors

Praveen Surendran, University of Cambridge
Elena V. Feofanova, University of Texas Health Science Center at Houston
Najim Lahrouchi, Broad Institute
Ioanna Ntalla, Barts and The London School of Medicine and Dentistry
Savita Karthikeyan, University of Cambridge
James Cook, University of Liverpool
Lingyan Chen, University of Cambridge
Borbala Mifsud, Barts and The London School of Medicine and Dentistry
Chen Yao, Framingham Heart Study
Aldi T. Kraja, Washington University School of Medicine in St. Louis
James H. Cartwright, Barts and The London School of Medicine and Dentistry
Jacklyn N. Hellwege, Vanderbilt University Medical Center
Ayush Giri, Vanderbilt University Medical Center
Vinicius Tragante, University Medical Center Utrecht
Gudmar Thorleifsson, deCODE genetics
Dajiang J. Liu, Penn State College of Medicine
Bram P. Prins, University of Cambridge
Isobel D. Stewart, School of Clinical Medicine
Claudia P. Cabrera, Barts and The London School of Medicine and Dentistry
James M. Eales, The University of Manchester
Artur Akbarov, The University of Manchester
Paul L. Auer, University of Wisconsin-Milwaukee
Lawrence F. Bielak, University of Michigan, Ann Arbor
Joshua C. Bis, University of Washington School of Medicine
Vickie S. Braithwaite, School of Clinical Medicine
Jennifer A. Brody, University of Washington School of Medicine
E. Warwick Daw, Washington University School of Medicine in St. Louis
Helen R. Warren, Barts and The London School of Medicine and Dentistry
Fotios Drenos, Brunel University London
Sune Fallgaard Nielsen, Amtssygehuset i Gentofte
Jessica D. Faul, University of Michigan, Ann Arbor
Eric B. Fauman, Pfizer Inc.

Document Type

Journal Article

Publication Date

12-1-2020

Journal

Nature Genetics

Volume

52

Issue

12

DOI

10.1038/s41588-020-00713-x

Abstract

© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc. 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.

APA Citation

Surendran, P., Feofanova, E., Lahrouchi, N., Ntalla, I., Karthikeyan, S., Cook, J., Chen, L., Mifsud, B., Yao, C., Kraja, A., Cartwright, J., Hellwege, J., Giri, A., Tragante, V., Thorleifsson, G., Liu, D., Prins, B., Stewart, I., Cabrera, C., Eales, J., Akbarov, A., Auer, P., Bielak, L., Bis, J., Braithwaite, V., Brody, J., Daw, E., Warren, H., Drenos, F., Nielsen, S., Faul, J., & Fauman, E. (2020). Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals. Nature Genetics, 52 (12). http://dx.doi.org/10.1038/s41588-020-00713-x