TY - JOUR
T1 - Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
AU - Million Veteran Program
AU - Lifelines Cohort Study
AU - EPIC-CVD
AU - EPIC-InterAct
AU - Understanding Society Scientific group
AU - Surendran, Praveen
AU - Feofanova, Elena V.
AU - Lahrouchi, Najim
AU - Ntalla, Ioanna
AU - Karthikeyan, Savita
AU - Cook, James
AU - Chen, Lingyan
AU - Mifsud, Borbala
AU - Yao, Chen
AU - Kraja, Aldi T.
AU - Cartwright, James H.
AU - Hellwege, Jacklyn N.
AU - Giri, Ayush
AU - Tragante, Vinicius
AU - Thorleifsson, Gudmar
AU - Liu, Dajiang J.
AU - Prins, Bram P.
AU - Stewart, Isobel D.
AU - Cabrera, Claudia P.
AU - Eales, James M.
AU - Akbarov, Artur
AU - Auer, Paul L.
AU - Bielak, Lawrence F.
AU - Bis, Joshua C.
AU - Braithwaite, Vickie S.
AU - Brody, Jennifer A.
AU - Daw, E. Warwick
AU - Warren, Helen R.
AU - Drenos, Fotios
AU - Nielsen, Sune Fallgaard
AU - Faul, Jessica D.
AU - Fauman, Eric B.
AU - Fava, Cristiano
AU - Ferreira, Teresa
AU - Foley, Christopher N.
AU - Franceschini, Nora
AU - Gao, He
AU - Giannakopoulou, Olga
AU - Giulianini, Franco
AU - Gudbjartsson, Daniel F.
AU - Guo, Xiuqing
AU - Harris, Sarah E.
AU - Havulinna, Aki S.
AU - Helgadottir, Anna
AU - Huffman, Jennifer E.
AU - Hwang, Shih Jen
AU - Kanoni, Stavroula
AU - Kontto, Jukka
AU - Larson, Martin G.
AU - Li-Gao, Ruifang
N1 - Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85096546970
U2 - 10.1038/s41588-020-00713-x
DO - 10.1038/s41588-020-00713-x
M3 - Article
C2 - 33230300
AN - SCOPUS:85096546970
SN - 1061-4036
VL - 52
SP - 1314
EP - 1332
JO - Nature Genetics
JF - Nature Genetics
IS - 12
ER -