Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension.
Surendran P., Drenos F., Young R., Warren H., Cook JP., Manning AK., Grarup N., Sim X., Barnes DR., Witkowska K., Staley JR., Tragante V., Tukiainen T., Yaghootkar H., Masca N., Freitag DF., Ferreira T., Giannakopoulou O., Tinker A., Harakalova M., Mihailov E., Liu C., Kraja AT., Fallgaard Nielsen S., Rasheed A., Samuel M., Zhao W., Bonnycastle LL., Jackson AU., Narisu N., Swift AJ., Southam L., Marten J., Huyghe JR., Stančáková A., Fava C., Ohlsson T., Matchan A., Stirrups KE., Bork-Jensen J., Gjesing AP., Kontto J., Perola M., Shaw-Hawkins S., Havulinna AS., Zhang H., Donnelly LA., Groves CJ., Rayner NW., Neville MJ., Robertson NR., Yiorkas AM., Herzig K-H., Kajantie E., Zhang W., Willems SM., Lannfelt L., Malerba G., Soranzo N., Trabetti E., Verweij N., Evangelou E., Moayyeri A., Vergnaud A-C., Nelson CP., Poveda A., Varga TV., Caslake M., de Craen AJ., Trompet S., Luan J., Scott RA., Harris SE., Liewald DC., Marioni R., Menni C., Farmaki A-E., Hallmans G., Renström F., Huffman JE., Hassinen M., Burgess S., Vasan RS., Felix JF., CHARGE-Heart Failure Consortium None., Uria-Nickelsen M., Malarstig A., Reily DF., Hoek M., Vogt T., Lin H., Lieb W., EchoGen Consortium None., Traylor M., Markus HF., METASTROKE Consortium None., Highland HM., Justice AE., Marouli E., GIANT Consortium None., Lindström J., Uusitupa M., Komulainen P., Lakka TA., Rauramaa R., Polasek O., Rudan I., Rolandsson O., Franks PW., Dedoussis G., Spector TD., EPIC-InterAct Consortium None., Jousilahti P., Männistö S., Deary IJ., Starr JM., Langenberg C., Wareham NJ., Brown MJ., Dominiczak AF., Connell JM., Jukema JW., Sattar N., Ford I., Packard CJ., Esko T., Mägi R., Metspalu A., de Boer RA., van der Meer P., van der Harst P., Lifelines Cohort Study None., Gambaro G., Ingelsson E., Lind L., de Bakker PI., Numans ME., Brandslund I., Christensen C., Petersen ER., Korpi-Hyövälti E., Oksa H., Chambers JC., Kooner JS., Blakemore AI., Franks S., Jarvelin M-R., Husemoen LL., Linneberg A., Skaaby T., Thuesen B., Karpe F., Tuomilehto J., Doney AS., Morris AD., Palmer CN., Holmen OL., Hveem K., Willer CJ., Tuomi T., Groop L., Käräjämäki A., Palotie A., Ripatti S., Salomaa V., Alam DS., Shafi Majumder AA., Di Angelantonio E., Chowdhury R., McCarthy MI., Poulter N., Stanton AV., Sever P., Amouyel P., Arveiler D., Blankenberg S., Ferrières J., Kee F., Kuulasmaa K., Müller-Nurasyid M., Veronesi G., Virtamo J., Deloukas P., Wellcome Trust Case Control Consortium None., Elliott P., Understanding Society Scientific Group None., Zeggini E., Kathiresan S., Melander O., Kuusisto J., Laakso M., Padmanabhan S., Porteous D., Hayward C., Scotland G., Collins FS., Mohlke KL., Hansen T., Pedersen O., Boehnke M., Stringham HM., EPIC-CVD Consortium None., Frossard P., Newton-Cheh C., CHARGE+ Exome Chip Blood Pressure Consortium None., Tobin MD., Nordestgaard BG., T2D-GENES Consortium None., GoT2DGenes Consortium None., ExomeBP Consortium None., CHD Exome+ Consortium None., Caulfield MJ., Mahajan A., Morris AP., Tomaszewski M., Samani NJ., Saleheen D., Asselbergs FW., Lindgren CM., Danesh J., Wain LV., Butterworth AS., Howson JM., Munroe PB.
High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we genotyped 242,296 rare, low-frequency and common genetic variants in up to 192,763 individuals and used ∼155,063 samples for independent replication. We identified 30 new blood pressure- or hypertension-associated genetic regions in the general population, including 3 rare missense variants in RBM47, COL21A1 and RRAS with larger effects (>1.5 mm Hg/allele) than common variants. Multiple rare nonsense and missense variant associations were found in A2ML1, and a low-frequency nonsense variant in ENPEP was identified. Our data extend the spectrum of allelic variation underlying blood pressure traits and hypertension, provide new insights into the pathophysiology of hypertension and indicate new targets for clinical intervention.