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

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency, MAF > 0.05). In a meta-analysis of up to >1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (MAF ≤ 0.01) variant BP associations (P < 5 × 10(-...

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Detalles Bibliográficos
Autores principales: Surendran, Praveen, Feofanova, Elena V., Lahrouchi, Najim, Ntalla, Ioanna, Karthikeyan, Savita, Cook, James, Chen, Lingyan, Mifsud, Borbala, Yao, Chen, Kraja, Aldi T., Cartwright, James H., Hellwege, Jacklyn N., Giri, Ayush, Tragante, Vinicius, Thorleifsson, Gudmar, Liu, Dajiang J., Prins, Bram P., Stewart, Isobel D., Cabrera, Claudia P., Eales, James M., Akbarov, Artur, Auer, Paul L., Bielak, Lawrence F., Bis, Joshua C., Braithwaite, Vickie S., Brody, Jennifer A., Daw, E. Warwick, Warren, Helen R., Drenos, Fotios, Nielsen, Sune Fallgaard, Faul, Jessica D., Fauman, Eric B., Fava, Cristiano, Ferreira, Teresa, Foley, Christopher N., Franceschini, Nora, Gao, He, Giannakopoulou, Olga, Giulianini, Franco, Gudbjartsson, Daniel F., Guo, Xiuqing, Harris, Sarah E., Havulinna, Aki S., Helgadottir, Anna, Huffman, Jennifer E., Hwang, Shih-Jen, Kanoni, Stavroula, Kontto, Jukka, Larson, Martin G., Li-Gao, Ruifang, Lindström, Jaana, Lotta, Luca A., Lu, Yingchang, Luan, Jian’an, Mahajan, Anubha, Malerba, Giovanni, Masca, Nicholas G. D., Mei, Hao, Menni, Cristina, Mook-Kanamori, Dennis O., Mosen-Ansorena, David, Müller-Nurasyid, Martina, Paré, Guillaume, Paul, Dirk S., Perola, Markus, Poveda, Alaitz, Rauramaa, Rainer, Richard, Melissa, Richardson, Tom G., Sepúlveda, Nuno, Sim, Xueling, Smith, Albert V., Smith, Jennifer A., Staley, James R., Stanáková, Alena, Sulem, Patrick, Thériault, Sébastien, Thorsteinsdottir, Unnur, Trompet, Stella, Varga, Tibor V., Velez Edwards, Digna R., Veronesi, Giovanni, Weiss, Stefan, Willems, Sara M., Yao, Jie, Young, Robin, Yu, Bing, Zhang, Weihua, Zhao, Jing-Hua, Zhao, Wei, Εvangelou, Evangelos, Aeschbacher, Stefanie, Asllanaj, Eralda, Blankenberg, Stefan, Bonnycastle, Lori L., Bork-Jensen, Jette, Brandslund, Ivan, Braund, Peter S., Burgess, Stephen, Cho, Kelly, Christensen, Cramer, Connell, John, de Mutsert, Renée, Dominiczak, Anna F., Dörr, Marcus, Eiriksdottir, Gudny, Farmaki, Aliki-Eleni, Gaziano, J. Michael, Grarup, Niels, Grove-Gaona, Megan L., Hallmans, Göran, Hansen, Torben, Have, Christian T., Heiss, Gerardo, Jørgensen, Marit E., Jousilahti, Pekka, Kajantie, Eero, Kamat, Mihir, Käräjämäki, AnneMari, Karpe, Fredrik, Koistinen, Heikki A., Kovesdy, Csaba P., Kuulasmaa, Kari, Laatikainen, Tiina, Lannfelt, Lars, Lee, I-Te, Lee, Wen-Jane, Linneberg, Allan, Martin, Lisa W., Moitry, Marie, Nadkarni, Girish, Neville, Matt J., Palmer, Colin N. A., Papanicolaou, George J., Pedersen, Oluf, Peters, James, Poulter, Neil, Rasheed, Asif, Rasmussen, Katrine L., Rayner, N. 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F., al Shafi Majumder, Abdulla, Laakso, Markku, McCarthy, Mark I., Melander, Olle, Mohlke, Karen L., Murray, Alison D., Nordestgaard, Børge Grønne, Orho-Melander, Marju, Packard, Chris J., Padmanabhan, Sandosh, Palmas, Walter, Polasek, Ozren, Porteous, David J., Prentice, Andrew M., Province, Michael A., Relton, Caroline L., Rice, Kenneth, Ridker, Paul M., Rolandsson, Olov, Rosendaal, Frits R., Rotter, Jerome I., Rudan, Igor, Salomaa, Veikko, Samani, Nilesh J., Sattar, Naveed, Sheu, Wayne H.-H., Smith, Blair H., Soranzo, Nicole, Spector, Timothy D., Starr, John M., Sylvain, Sebert, Taylor, Kent D., Lakka, Timo A., Timpson, Nicholas J., Tobin, Martin D., van der Harst, Pim, van der Meer, Peter, Vasan, Ramachandran S., Verweij, Niek, Virtamo, Jarmo, Völker, Uwe, Weir, David R., Zeggini, Eleftheria, Charchar, Fadi J., Wareham, Nicholas J., Langenberg, Claudia, Tomaszewski, Maciej, Butterworth, Adam S., Caulfield, Mark J., Danesh, John, Edwards, Todd L., Holm, Hilma, Hung, Adriana M., Lindgren, Cecilia M., Liu, Chunyu, Manning, Alisa K., Morris, Andrew P., Morrison, Alanna C., O’Donnell, Christopher J., Psaty, Bruce M., Saleheen, Danish, Stefansson, Kari, Boerwinkle, Eric, Chasman, Daniel I., Levy, Daniel, Newton-Cheh, Christopher, Munroe, Patricia B., Howson, Joanna M. 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Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439/
https://www.ncbi.nlm.nih.gov/pubmed/33230300
http://dx.doi.org/10.1038/s41588-020-00713-x
Descripción
Sumario:Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency, MAF > 0.05). In a meta-analysis of up to >1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (MAF ≤ 0.01) variant BP associations (P < 5 × 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated SNVs 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 (e.g. GATA5, 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.