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 > 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 ...

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Vydáno v:	Nature genetics Ročník 52; číslo 12; s. 1314 - 1332
Hlavní autoři:	Ntalla, Ioanna, Karthikeyan, Savita, Mifsud, Borbala, Kraja, Aldi T., Cartwright, James H., Hellwege, Jacklyn N., Giri, Ayush, Tragante, Vinicius, Prins, Bram P., Cabrera, Claudia P., Eales, James M., Akbarov, Artur, Bielak, Lawrence F., Brody, Jennifer A., Drenos, Fotios, Nielsen, Sune Fallgaard, Faul, Jessica D., Franceschini, Nora, Gao, He, Giulianini, Franco, Hwang, Shih-Jen, Kanoni, Stavroula, Lindström, Jaana, Luan, Jian’an, Mahajan, Anubha, Malerba, Giovanni, Perola, Markus, Richard, Melissa, Richardson, Tom G., Sepúlveda, Nuno, Thériault, Sébastien, Trompet, Stella, Varga, Tibor V., Velez Edwards, Digna R., Veronesi, Giovanni, Weiss, Stefan, Willems, Sara M., Young, Robin, Zhang, Weihua, Zhao, Wei, Evangelou, Evangelos, Aeschbacher, Stefanie, Asllanaj, Eralda, Mutsert, Renée de, Dörr, Marcus, Gaziano, J. Michael, Have, Christian T., Kajantie, Eero, Kamat, Mihir, Karpe, Fredrik, Koistinen, Heikki A., Moitry, Marie, Peters, James, Rossouw, Jacques, Sever, Peter S., Sigurdsson, Emil L., Skaaby, Tea, Sun, Yan V., Trabetti, Elisabetta, Vaartjes, Ilonca, Buring, Julie E., Chowdhury, Rajiv, Correa, Adolfo, Deary, Ian J., Deloukas, Panos, Ferrières, Jean, Fornage, Myriam, Gaunt, Tom R., Harris, Tamara B., Järvelin, Marjo-Riitta, Kooperberg, Charles, Launer, Lenore J., Majumder, Abdulla al Shafi, Laakso, Markku, Melander, Olle, Mohlke, Karen L., Orho-Melander, Marju, Palmas, Walter, Polasek, Ozren, Province, Michael A., Rolandsson, Olov, Rosendaal, Frits R., Rotter, Jerome I., Samani, Nilesh J., Soranzo, Nicole, Spector, Timothy D., Starr, John M., van der Harst, Pim, van der Meer, Peter, Verweij, Niek, Virtamo, Jarmo, Wareham, Nicholas J., Langenberg, Claudia, Liu, Chunyu, Manning, Alisa K., Morrison, Alanna C., O’Donnell, Christopher J., Saleheen, Danish, Boerwinkle, Eric, Chasman, Daniel I.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	New York Nature Publishing Group US 01.12.2020 Nature Publishing Group
Témata:	38/39 45/43 631/208 631/208/205 631/208/205/2138 692/699/75/243 Agriculture Alleles Animal Genetics and Genomics Basic Medicine Biomedical and Life Sciences Biomedicine Blood pressure Blood Pressure - genetics Cancer Research Cardiology and Cardiovascular Disease Chromatin Clinical Medicine Fetuses GATA5 Transcription Factor - genetics Gene frequency Gene Frequency - genetics Gene Function Genes Genetic Predisposition to Disease - genetics Genetic variation Genome-Wide Association Study Genomes Genotype Health aspects Human Genetics Humans Hypertension - genetics Identification and classification Kardiologi och kardiovaskulära sjukdomar Klinisk medicin Life Sciences Loci Management Medical and Health Sciences Medical Genetics and Genomics (including Gene Therapy) Medicin och hälsovetenskap Medicinsk genetik och genomik (Här ingår: Genterapi) Medicinska och farmaceutiska grundvetenskaper Meta-analysis Mutation - genetics Nucleotides Phospholipase C beta - genetics Polymorphism, Single Nucleotide - genetics Regulation Secondary data analysis Netherlands
ISSN:	1061-4036, 1546-1718, 1546-1718
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Popis
Shrnutí:	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. Meta-analyses in up to 1.3 million individuals identify 87 rare-variant associations with blood pressure traits. On average, rare variants exhibit effects ~8 times larger than the mean effects of common variants and implicate candidate causal genes at associated regions.
Bibliografie:	ObjectType-Article-1 ObjectType-Evidence Based Healthcare-3 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 PMCID: PMC7610439 These authors jointly supervised the work. Current address (if different to the affiliations), Mark McCarthy: Genentech, South San Francisco, CA, USA.
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-020-00713-x