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

LifeLines Cohort Study, EPIC-CVD Consortium, EPIC-InterAct Consortium, Understanding Society Scientific Group, Million Veteran Program, Praveen Surendran, Elena V. Feofanova, Najim Lahrouchi, Ioanna Ntalla, Savita Karthikeyan, James Cook, Lingyan Chen, Borbala Mifsud, Chen Yao, Aldi T. Kraja, James H. Cartwright, Jacklyn N. Hellwege, Ayush Giri, Vinicius Tragante, Gudmar ThorleifssonDajiang J. Liu, Bram P. Prins, Isobel D. Stewart, Claudia P. Cabrera, James M. Eales, Artur Akbarov, Paul L. Auer, Lawrence F. Bielak, Joshua C Bis, Vickie S Braithwaite, Jennifer A Brody, E Warwick Daw, Helen R Warren, Fotios Drenos, Sune Fallgaard Nielsen, Jessica D Faul, Eric B Fauman, Cristiano Fava, Teresa Ferreira, Christopher N Foley, Nora Franceschini, He Gao, Olga Giannakopoulou, Franco Giulianini, Daniel F Gudbjartsson, Xiuqing Guo, Sarah E Harris, Aki S Havulinna, Anna Helgadottir, Jennifer E Huffman, Shih-Jen Hwang, Stavroula Kanoni, Jennifer A Smith, Colin N A Palmer, Blair H Smith, Patricia B. Munroe (Lead / Corresponding author), Joanna M. M. Howson (Lead / Corresponding author)

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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.

Original languageEnglish
Pages (from-to)1314-1332
Number of pages19
JournalNature Genetics
Issue number12
Early online date23 Nov 2020
Publication statusPublished - Dec 2020

ASJC Scopus subject areas

  • Genetics


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