Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Praveen Surendran; Fotios Drenos; Robin Young; Helen Warren; James P Cook; Alisa K Manning; Niels Grarup; Xueling Sim; Daniel R Barnes; Kate Witkowska; James R Staley; Vinicius Tragante; Taru Tukiainen; Hanieh Yaghootkar; Nicholas Masca; Daniel F Freitag; Teresa Ferreira; Olga Giannakopoulou; Andrew Tinker; Magdalena Harakalova; Evelin Mihailov; Chunyu Liu; Aldi T Kraja; Sune Fallgaard Nielsen; Asif Rasheed; Maria Samuel; Wei Zhao; Lori L Bonnycastle; Anne U Jackson; Narisu Narisu; Amy J Swift; Lorraine Southam; Jonathan Marten; Jeroen R Huyghe; Alena Stančáková; Cristiano Fava; Therese Ohlsson; Angela Matchan; Kathleen E Stirrups; Jette Bork-Jensen; Anette P Gjesing; Jukka Kontto; Markus Perola; Susan Shaw-Hawkins; Aki S Havulinna; Lise L Husemoen; Allan Linneberg; Torben Hansen; Oluf Pedersen; Børge Grønne Nordestgaard; CHARGE-Heart Failure Consortium

doi:10.1038/ng.3654

Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Praveen Surendran, Fotios Drenos, Robin Young, Helen Warren, James P Cook, Alisa K Manning, Niels Grarup, Xueling Sim, Daniel R Barnes, Kate Witkowska, James R Staley, Vinicius Tragante, Taru Tukiainen, Hanieh Yaghootkar, Nicholas Masca, Daniel F Freitag, Teresa Ferreira, Olga Giannakopoulou, Andrew Tinker, Magdalena HarakalovaEvelin Mihailov, Chunyu Liu, Aldi T Kraja, Sune Fallgaard Nielsen, Asif Rasheed, Maria Samuel, Wei Zhao, Lori L Bonnycastle, Anne U Jackson, Narisu Narisu, Amy J Swift, Lorraine Southam, Jonathan Marten, Jeroen R Huyghe, Alena Stančáková, Cristiano Fava, Therese Ohlsson, Angela Matchan, Kathleen E Stirrups, Jette Bork-Jensen, Anette P Gjesing, Jukka Kontto, Markus Perola, Susan Shaw-Hawkins, Aki S Havulinna, Lise L Husemoen, Allan Linneberg, Torben Hansen, Oluf Pedersen, Børge Grønne Nordestgaard, CHARGE-Heart Failure Consortium

142 Citations (Scopus)

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
Journal	Nature Genetics
Volume	48
Issue number	10
Pages (from-to)	1151-1161
Number of pages	11
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.3654
Publication status	Published - 1 Oct 2016

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Surendran, P., Drenos, F., Young, R., Warren, H., Cook, J. P., Manning, A. K., Grarup, N., Sim, X., Barnes, D. R., Witkowska, K., Staley, J. R., Tragante, V., Tukiainen, T., Yaghootkar, H., Masca, N., Freitag, D. F., Ferreira, T., Giannakopoulou, O., Tinker, A., ... CHARGE-Heart Failure Consortium (2016). Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension. Nature Genetics, 48(10), 1151-1161. https://doi.org/10.1038/ng.3654

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, Nielsen, SF, 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, Husemoen, LL, Linneberg, A , Hansen, T , Pedersen, O , Nordestgaard, BG & CHARGE-Heart Failure Consortium 2016, 'Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension', Nature Genetics, vol. 48, no. 10, pp. 1151-1161. https://doi.org/10.1038/ng.3654

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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.",

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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 - Husemoen, Lise L

AU - Linneberg, Allan

AU - Hansen, Torben

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AU - Nordestgaard, Børge Grønne

AU - CHARGE-Heart Failure Consortium

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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.

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DO - 10.1038/ng.3654

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SN - 1061-4036

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EP - 1161

JO - Nature: New biology

JF - Nature: New biology

IS - 10

ER -

Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension

Abstract

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