Abstract
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 -1/4155,063 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.
| Original language | English |
|---|---|
| Pages (from-to) | 1151-1161 |
| Number of pages | 11 |
| Journal | Nature Genetics |
| Volume | 48 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 1 2016 |
| Externally published | Yes |
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Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension. / Surendran, Praveen; Drenos, Fotios; Young, Robin; Warren, Helen; Cook, James P.; Manning, Alisa K.; Grarup, Niels; Sim, Xueling; Barnes, Daniel R.; Witkowska, Kate; Staley, James R.; Tragante, Vinicius; Tukiainen, Taru; Yaghootkar, Hanieh; Masca, Nicholas; Freitag, Daniel F.; Ferreira, Teresa; Giannakopoulou, Olga; Tinker, Andrew; Harakalova, Magdalena; Mihailov, Evelin; Liu, Chunyu; Kraja, Aldi T.; Nielsen, Sune Fallgaard; Rasheed, Asif; Samuel, Maria; Zhao, Wei; Bonnycastle, Lori L.; Jackson, Anne U.; Narisu, Narisu; Swift, Amy J.; Southam, Lorraine; Marten, Jonathan; Huyghe, Jeroen R.; Stančáková, Alena; Fava, Cristiano; Ohlsson, Therese; Matchan, Angela; Stirrups, Kathleen E.; Bork-Jensen, Jette; Gjesing, Anette P.; Kontto, Jukka; Perola, Markus; Shaw-Hawkins, Susan; Havulinna, Aki S.; Zhang, He; Donnelly, Louise A.; Groves, Christopher J.; Rayner, N. William; Neville, Matt J.; Robertson, Neil R.; Yiorkas, Andrianos M.; Herzig, Karl Heinz; Kajantie, Eero; Zhang, Weihua; Willems, Sara M.; Lannfelt, Lars; Malerba, Giovanni; Soranzo, Nicole; Trabetti, Elisabetta; Verweij, Niek; Evangelou, Evangelos; Moayyeri, Alireza; Vergnaud, Anne Claire; Nelson, Christopher P.; Poveda, Alaitz; Varga, Tibor V.; Caslake, Muriel; De Craen, Anton J.M.; Trompet, Stella; Luan, Jian'An; Scott, Robert A.; Harris, Sarah E.; Liewald, David C.M.; Marioni, Riccardo; Menni, Cristina; Farmaki, Aliki Eleni; Hallmans, Göran; Renström, Frida; Huffman, Jennifer E.; Hassinen, Maija; Burgess, Stephen; Vasan, Ramachandran S.; Felix, Janine F.; Uria-Nickelsen, Maria; Malarstig, Anders; Reilly, Dermot F.; Hoek, Maarten; Vogt, Thomas F.; Lin, Honghuang; Lieb, Wolfgang; Traylor, Matthew; Markus, Hugh S.; Highland, Heather M.; Justice, Anne E.; Marouli, Eirini; Lindström, Jaana; Uusitupa, Matti; Komulainen, Pirjo; Lakka, Timo A.; Rauramaa, Rainer; Polasek, Ozren; Rudan, Igor; Rolandsson, Olov; Franks, Paul W.; Dedoussis, George; Spector, Timothy D.; Jousilahti, Pekka; Männistö, Satu; Deary, Ian J.; Starr, John M.; Langenberg, Claudia; Wareham, Nick J.; Brown, Morris J.; Dominiczak, Anna F.; Connell, John M.; Jukema, J. Wouter; Sattar, Naveed; Ford, Ian; Packard, Chris J.; Esko, Tõnu; Mägi, Reedik; Metspalu, Andres; De Boer, Rudolf A.; Van Der Meer, Peter; Van Der Harst, Pim; Gambaro, Giovanni; Ingelsson, Erik; Lind, Lars; De Bakker, Paul I.W.; Numans, Mattijs E.; Brandslund, Ivan; Christensen, Cramer; Petersen, Eva R.B.; Korpi-Hyövälti, Eeva; Oksa, Heikki; Chambers, John C.; Kooner, Jaspal S.; Blakemore, Alexandra I.F.; Franks, Steve; Jarvelin, Marjo Riitta; Husemoen, Lise L.; Linneberg, Allan; Skaaby, Tea; Thuesen, Betina; Karpe, Fredrik; Tuomilehto, Jaakko; Doney, Alex S.F.; Morris, Andrew D.; Palmer, Colin N.A.; Holmen, Oddgeir Lingaas; Hveem, Kristian; Willer, Cristen J.; Tuomi, Tiinamaija; Groop, Leif; Käräjämäki, Annemari; Palotie, Aarno; Ripatti, Samuli; Salomaa, Veikko; Alam, Dewan S.; Majumder, Abdulla Al Shafi; Di Angelantonio, Emanuele; Chowdhury, Rajiv; McCarthy, Mark I.; Poulter, Neil; Stanton, Alice V.; Sever, Peter; Amouyel, Philippe; Arveiler, Dominique; Blankenberg, Stefan; Ferrières, Jean; Kee, Frank; Kuulasmaa, Kari; Müller-Nurasyid, Martina; Veronesi, Giovanni; Virtamo, Jarmo; Deloukas, Panos; Elliott, Paul; Zeggini, Eleftheria; Kathiresan, Sekar; Melander, Olle; Kuusisto, Johanna; Laakso, Markku; Padmanabhan, Sandosh; Porteous, David J.; Hayward, Caroline; Scotland, Generation; Collins, Francis S.; Mohlke, Karen L.; Hansen, Torben; Pedersen, Oluf; Boehnke, Michael; Stringham, Heather M.; Frossard, Philippe; Newton-Cheh, Christopher; Tobin, Martin D.; Nordestgaard, Børge Grønne; Caulfield, Mark J.; Mahajan, Anubha; Morris, Andrew P.; Tomaszewski, Maciej; Samani, Nilesh J.; Saleheen, Danish; Asselbergs, Folkert W.; Lindgren, Cecilia M.; Danesh, John; Wain, Louise V.; Butterworth, Adam S.; Howson, Joanna M.M.; Munroe, Patricia B.
In: Nature Genetics, Vol. 48, No. 10, 01.10.2016, p. 1151-1161.Research output: Contribution to journal › Article
TY - JOUR
T1 - Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension
AU - Surendran, Praveen
AU - Drenos, Fotios
AU - Young, Robin
AU - Warren, Helen
AU - Cook, James P.
AU - Manning, Alisa K.
AU - Grarup, Niels
AU - Sim, Xueling
AU - Barnes, Daniel R.
AU - Witkowska, Kate
AU - Staley, James R.
AU - Tragante, Vinicius
AU - Tukiainen, Taru
AU - Yaghootkar, Hanieh
AU - Masca, Nicholas
AU - Freitag, Daniel F.
AU - Ferreira, Teresa
AU - Giannakopoulou, Olga
AU - Tinker, Andrew
AU - Harakalova, Magdalena
AU - Mihailov, Evelin
AU - Liu, Chunyu
AU - Kraja, Aldi T.
AU - Nielsen, Sune Fallgaard
AU - Rasheed, Asif
AU - Samuel, Maria
AU - Zhao, Wei
AU - Bonnycastle, Lori L.
AU - Jackson, Anne U.
AU - Narisu, Narisu
AU - Swift, Amy J.
AU - Southam, Lorraine
AU - Marten, Jonathan
AU - Huyghe, Jeroen R.
AU - Stančáková, Alena
AU - Fava, Cristiano
AU - Ohlsson, Therese
AU - Matchan, Angela
AU - Stirrups, Kathleen E.
AU - Bork-Jensen, Jette
AU - Gjesing, Anette P.
AU - Kontto, Jukka
AU - Perola, Markus
AU - Shaw-Hawkins, Susan
AU - Havulinna, Aki S.
AU - Zhang, He
AU - Donnelly, Louise A.
AU - Groves, Christopher J.
AU - Rayner, N. William
AU - Neville, Matt J.
AU - Robertson, Neil R.
AU - Yiorkas, Andrianos M.
AU - Herzig, Karl Heinz
AU - Kajantie, Eero
AU - Zhang, Weihua
AU - Willems, Sara M.
AU - Lannfelt, Lars
AU - Malerba, Giovanni
AU - Soranzo, Nicole
AU - Trabetti, Elisabetta
AU - Verweij, Niek
AU - Evangelou, Evangelos
AU - Moayyeri, Alireza
AU - Vergnaud, Anne Claire
AU - Nelson, Christopher P.
AU - Poveda, Alaitz
AU - Varga, Tibor V.
AU - Caslake, Muriel
AU - De Craen, Anton J.M.
AU - Trompet, Stella
AU - Luan, Jian'An
AU - Scott, Robert A.
AU - Harris, Sarah E.
AU - Liewald, David C.M.
AU - Marioni, Riccardo
AU - Menni, Cristina
AU - Farmaki, Aliki Eleni
AU - Hallmans, Göran
AU - Renström, Frida
AU - Huffman, Jennifer E.
AU - Hassinen, Maija
AU - Burgess, Stephen
AU - Vasan, Ramachandran S.
AU - Felix, Janine F.
AU - Uria-Nickelsen, Maria
AU - Malarstig, Anders
AU - Reilly, Dermot F.
AU - Hoek, Maarten
AU - Vogt, Thomas F.
AU - Lin, Honghuang
AU - Lieb, Wolfgang
AU - Traylor, Matthew
AU - Markus, Hugh S.
AU - Highland, Heather M.
AU - Justice, Anne E.
AU - Marouli, Eirini
AU - Lindström, Jaana
AU - Uusitupa, Matti
AU - Komulainen, Pirjo
AU - Lakka, Timo A.
AU - Rauramaa, Rainer
AU - Polasek, Ozren
AU - Rudan, Igor
AU - Rolandsson, Olov
AU - Franks, Paul W.
AU - Dedoussis, George
AU - Spector, Timothy D.
AU - Jousilahti, Pekka
AU - Männistö, Satu
AU - Deary, Ian J.
AU - Starr, John M.
AU - Langenberg, Claudia
AU - Wareham, Nick J.
AU - Brown, Morris J.
AU - Dominiczak, Anna F.
AU - Connell, John M.
AU - Jukema, J. Wouter
AU - Sattar, Naveed
AU - Ford, Ian
AU - Packard, Chris J.
AU - Esko, Tõnu
AU - Mägi, Reedik
AU - Metspalu, Andres
AU - De Boer, Rudolf A.
AU - Van Der Meer, Peter
AU - Van Der Harst, Pim
AU - Gambaro, Giovanni
AU - Ingelsson, Erik
AU - Lind, Lars
AU - De Bakker, Paul I.W.
AU - Numans, Mattijs E.
AU - Brandslund, Ivan
AU - Christensen, Cramer
AU - Petersen, Eva R.B.
AU - Korpi-Hyövälti, Eeva
AU - Oksa, Heikki
AU - Chambers, John C.
AU - Kooner, Jaspal S.
AU - Blakemore, Alexandra I.F.
AU - Franks, Steve
AU - Jarvelin, Marjo Riitta
AU - Husemoen, Lise L.
AU - Linneberg, Allan
AU - Skaaby, Tea
AU - Thuesen, Betina
AU - Karpe, Fredrik
AU - Tuomilehto, Jaakko
AU - Doney, Alex S.F.
AU - Morris, Andrew D.
AU - Palmer, Colin N.A.
AU - Holmen, Oddgeir Lingaas
AU - Hveem, Kristian
AU - Willer, Cristen J.
AU - Tuomi, Tiinamaija
AU - Groop, Leif
AU - Käräjämäki, Annemari
AU - Palotie, Aarno
AU - Ripatti, Samuli
AU - Salomaa, Veikko
AU - Alam, Dewan S.
AU - Majumder, Abdulla Al Shafi
AU - Di Angelantonio, Emanuele
AU - Chowdhury, Rajiv
AU - McCarthy, Mark I.
AU - Poulter, Neil
AU - Stanton, Alice V.
AU - Sever, Peter
AU - Amouyel, Philippe
AU - Arveiler, Dominique
AU - Blankenberg, Stefan
AU - Ferrières, Jean
AU - Kee, Frank
AU - Kuulasmaa, Kari
AU - Müller-Nurasyid, Martina
AU - Veronesi, Giovanni
AU - Virtamo, Jarmo
AU - Deloukas, Panos
AU - Elliott, Paul
AU - Zeggini, Eleftheria
AU - Kathiresan, Sekar
AU - Melander, Olle
AU - Kuusisto, Johanna
AU - Laakso, Markku
AU - Padmanabhan, Sandosh
AU - Porteous, David J.
AU - Hayward, Caroline
AU - Scotland, Generation
AU - Collins, Francis S.
AU - Mohlke, Karen L.
AU - Hansen, Torben
AU - Pedersen, Oluf
AU - Boehnke, Michael
AU - Stringham, Heather M.
AU - Frossard, Philippe
AU - Newton-Cheh, Christopher
AU - Tobin, Martin D.
AU - Nordestgaard, Børge Grønne
AU - Caulfield, Mark J.
AU - Mahajan, Anubha
AU - Morris, Andrew P.
AU - Tomaszewski, Maciej
AU - Samani, Nilesh J.
AU - Saleheen, Danish
AU - Asselbergs, Folkert W.
AU - Lindgren, Cecilia M.
AU - Danesh, John
AU - Wain, Louise V.
AU - Butterworth, Adam S.
AU - Howson, Joanna M.M.
AU - Munroe, Patricia B.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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 -1/4155,063 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.
AB - 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 -1/4155,063 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.
UR - http://www.scopus.com/inward/record.url?scp=84987670072&partnerID=8YFLogxK
U2 - 10.1038/ng.3654
DO - 10.1038/ng.3654
M3 - Article
C2 - 27618447
AN - SCOPUS:84987670072
VL - 48
SP - 1151
EP - 1161
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 10
ER -