New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals

Aldi T. Kraja; James P. Cook; Helen R. Warren; Praveen Surendran; Chunyu Liu; Evangelos Evangelou; Alisa K. Manning; Niels Grarup; Fotios Drenos; Xueling Sim; Albert Vernon Smith; Najaf Amin; Alexandra I.F. Blakemore; Jette Bork-Jensen; Ivan Brandslund; Aliki Eleni Farmaki; Cristiano Fava; Teresa Ferreira; Karl Heinz Herzig; Ayush Giri; Franco Giulianini; Megan L. Grove; Xiuqing Guo; Sarah E. Harris; Christian T. Have; Aki S. Havulinna; He Zhang; Marit E. Jørgensen; Anne Mari Käräjämäki; Charles Kooperberg; Allan Linneberg; Louis Little; Yongmei Liu; Lori L. Bonnycastle; Yingchang Lu; Reedik Mägi; Anubha Mahajan; Giovanni Malerba; Riccardo E. Marioni; Hao Mei; Cristina Menni; Alanna C. Morrison; Sandosh Padmanabhan; Walter Palmas; Alaitz Poveda; Rainer Rauramaa; Nigel William Rayner; Muhammad Riaz; Torben Hansen; Oluf Pedersen; behalf of the CHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group

doi:10.1161/circgenetics.117.001778

New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals

Aldi T. Kraja^*, James P. Cook, Helen R. Warren, Praveen Surendran, Chunyu Liu, Evangelos Evangelou, Alisa K. Manning, Niels Grarup, Fotios Drenos, Xueling Sim, Albert Vernon Smith, Najaf Amin, Alexandra I.F. Blakemore, Jette Bork-Jensen, Ivan Brandslund, Aliki Eleni Farmaki, Cristiano Fava, Teresa Ferreira, Karl Heinz Herzig, Ayush GiriFranco Giulianini, Megan L. Grove, Xiuqing Guo, Sarah E. Harris, Christian T. Have, Aki S. Havulinna, He Zhang, Marit E. Jørgensen, Anne Mari Käräjämäki, Charles Kooperberg, Allan Linneberg, Louis Little, Yongmei Liu, Lori L. Bonnycastle, Yingchang Lu, Reedik Mägi, Anubha Mahajan, Giovanni Malerba, Riccardo E. Marioni, Hao Mei, Cristina Menni, Alanna C. Morrison, Sandosh Padmanabhan, Walter Palmas, Alaitz Poveda, Rainer Rauramaa, Nigel William Rayner, Muhammad Riaz, Torben Hansen, Oluf Pedersen, behalf of the CHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group

^*Corresponding author for this work

Department of Clinical Medicine

31 Citations (Scopus)

Abstract

Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results - Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10^-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant. Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

Original language	English
Article number	e001778
Journal	Circulation: Cardiovascular Genetics
Volume	10
Issue number	5
Number of pages	9
ISSN	1942-325X
DOIs	https://doi.org/10.1161/circgenetics.117.001778
Publication status	Published - Oct 2017

Keywords

blood pressure
exome
genetics
genotype
sample size

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Kraja, A. T., Cook, J. P., Warren, H. R., Surendran, P., Liu, C., Evangelou, E., Manning, A. K., Grarup, N., Drenos, F., Sim, X., Smith, A. V., Amin, N., Blakemore, A. I. F., Bork-Jensen, J., Brandslund, I., Farmaki, A. E., Fava, C., Ferreira, T., Herzig, K. H., ... behalf of the CHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group (2017). New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals. Circulation: Cardiovascular Genetics, 10(5), [e001778]. https://doi.org/10.1161/circgenetics.117.001778

Kraja, AT, Cook, JP, Warren, HR, Surendran, P, Liu, C, Evangelou, E, Manning, AK, Grarup, N, Drenos, F, Sim, X, Smith, AV, Amin, N, Blakemore, AIF, Bork-Jensen, J, Brandslund, I, Farmaki, AE, Fava, C, Ferreira, T, Herzig, KH, Giri, A, Giulianini, F, Grove, ML, Guo, X, Harris, SE, Have, CT, Havulinna, AS, Zhang, H, Jørgensen, ME, Käräjämäki, AM, Kooperberg, C, Linneberg, A, Little, L, Liu, Y, Bonnycastle, LL, Lu, Y, Mägi, R, Mahajan, A, Malerba, G, Marioni, RE, Mei, H, Menni, C, Morrison, AC, Padmanabhan, S, Palmas, W, Poveda, A, Rauramaa, R, Rayner, NW, Riaz, M, Hansen, T , Pedersen, O & behalf of the CHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group 2017, 'New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals', Circulation: Cardiovascular Genetics, vol. 10, no. 5, e001778. https://doi.org/10.1161/circgenetics.117.001778

@article{cdd2b37410a943d09d400689643d139c,

title = "New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals",

abstract = "Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results - Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant. Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.",

keywords = "blood pressure, exome, genetics, genotype, sample size",

author = "Kraja, {Aldi T.} and Cook, {James P.} and Warren, {Helen R.} and Praveen Surendran and Chunyu Liu and Evangelos Evangelou and Manning, {Alisa K.} and Niels Grarup and Fotios Drenos and Xueling Sim and Smith, {Albert Vernon} and Najaf Amin and Blakemore, {Alexandra I.F.} and Jette Bork-Jensen and Ivan Brandslund and Farmaki, {Aliki Eleni} and Cristiano Fava and Teresa Ferreira and Herzig, {Karl Heinz} and Ayush Giri and Franco Giulianini and Grove, {Megan L.} and Xiuqing Guo and Harris, {Sarah E.} and Have, {Christian T.} and Havulinna, {Aki S.} and He Zhang and J{\o}rgensen, {Marit E.} and K{\"a}r{\"a}j{\"a}m{\"a}ki, {Anne Mari} and Charles Kooperberg and Allan Linneberg and Louis Little and Yongmei Liu and Bonnycastle, {Lori L.} and Yingchang Lu and Reedik M{\"a}gi and Anubha Mahajan and Giovanni Malerba and Marioni, {Riccardo E.} and Hao Mei and Cristina Menni and Morrison, {Alanna C.} and Sandosh Padmanabhan and Walter Palmas and Alaitz Poveda and Rainer Rauramaa and Rayner, {Nigel William} and Muhammad Riaz and Torben Hansen and Oluf Pedersen and {behalf of the CHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group}",

year = "2017",

month = oct,

doi = "10.1161/circgenetics.117.001778",

language = "English",

volume = "10",

journal = "Circulation: Cardiovascular Genetics",

issn = "1942-325X",

publisher = "Lippincott Williams & Wilkins",

number = "5",

}

TY - JOUR

T1 - New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals

AU - Kraja, Aldi T.

AU - Cook, James P.

AU - Warren, Helen R.

AU - Surendran, Praveen

AU - Liu, Chunyu

AU - Evangelou, Evangelos

AU - Manning, Alisa K.

AU - Grarup, Niels

AU - Drenos, Fotios

AU - Sim, Xueling

AU - Smith, Albert Vernon

AU - Amin, Najaf

AU - Blakemore, Alexandra I.F.

AU - Bork-Jensen, Jette

AU - Brandslund, Ivan

AU - Farmaki, Aliki Eleni

AU - Fava, Cristiano

AU - Ferreira, Teresa

AU - Herzig, Karl Heinz

AU - Giri, Ayush

AU - Giulianini, Franco

AU - Grove, Megan L.

AU - Guo, Xiuqing

AU - Harris, Sarah E.

AU - Have, Christian T.

AU - Havulinna, Aki S.

AU - Zhang, He

AU - Jørgensen, Marit E.

AU - Käräjämäki, Anne Mari

AU - Kooperberg, Charles

AU - Linneberg, Allan

AU - Little, Louis

AU - Liu, Yongmei

AU - Bonnycastle, Lori L.

AU - Lu, Yingchang

AU - Mägi, Reedik

AU - Mahajan, Anubha

AU - Malerba, Giovanni

AU - Marioni, Riccardo E.

AU - Mei, Hao

AU - Menni, Cristina

AU - Morrison, Alanna C.

AU - Padmanabhan, Sandosh

AU - Palmas, Walter

AU - Poveda, Alaitz

AU - Rauramaa, Rainer

AU - Rayner, Nigel William

AU - Riaz, Muhammad

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - behalf of the CHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group

PY - 2017/10

Y1 - 2017/10

N2 - Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results - Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant. Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

AB - Background - Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. Methods and Results - Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant. Conclusions - We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.

KW - blood pressure

KW - exome

KW - genetics

KW - genotype

KW - sample size

U2 - 10.1161/circgenetics.117.001778

DO - 10.1161/circgenetics.117.001778

M3 - Journal article

C2 - 29030403

AN - SCOPUS:85032923056

SN - 1942-325X

VL - 10

JO - Circulation: Cardiovascular Genetics

JF - Circulation: Cardiovascular Genetics

IS - 5

M1 - e001778

ER -

New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals

Abstract

Keywords

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