Gene-age interactions in blood pressure regulation: A large-scale investigation with the CHARGE, global BPgen, and ICBP consortia

Jeannette Simino; Gang Shi; Joshua C. Bis; Daniel I. Chasman; Georg B. Ehret; Xiangjun Gu; Xiuqing Guo; Shih Jen Hwang; Eric Sijbrands; Albert V. Smith; Germaine C. Verwoert; Jennifer L. Bragg-Gresham; Gemma Cadby; Peng Chen; Ching Yu Cheng; Tanguy Corre; Rudolf A. De Boer; Anuj Goel; Toby Johnson; Chiea Chuen Khor; Carla Lluís-Ganella; Jian'An Luan; Leo Pekka Lyytikäinen; Ilja M. Nolte; Xueling Sim; Siim Sõber; Peter J. Van Der Most; Niek Verweij; Jing Hua Zhao; Najaf Amin; Eric Boerwinkle; Claude Bouchard; Abbas Dehghan; Gudny Eiriksdottir; Roberto Elosua; Oscar H. Franco; Christian Gieger; Tamara B. Harris; Serge Hercberg; Albert Hofman; Alan L. James; Andrew D. Johnson; Mika Kähönen; Kay Tee Khaw; Zoltan Kutalik; Martin G. Larson; Lenore J. Launer; Guo Li; Jianjun Liu; Kiang Liu; Alanna C. Morrison; Gerjan Navis; Rick Twee Hee Ong; George J. Papanicolau; Brenda W. Penninx; Bruce M. Psaty; Leslie J. Raffel; Olli T. Raitakari; Kenneth Rice; Fernando Rivadeneira; Lynda M. Rose; Serena Sanna; Robert A. Scott; David S. Siscovick; Ronald P. Stolk; Andre G. Uitterlinden; Dhananjay Vaidya; Melanie M. Van Der Klauw; Ramachandran S. Vasan; Eranga Nishanthie Vithana; Uwe Völker; Henry Völzke; Hugh Watkins; Terri L. Young; Tin Aung; Murielle Bochud; Martin Farrall; Catharina A. Hartman; Maris Laan; Edward G. Lakatta; Terho Lehtimäki; Ruth J.F. Loos; Gavin Lucas; Pierre Meneton; Lyle J. Palmer; Rainer Rettig; Harold Snieder; E. Shyong Tai; Yik Ying Teo; Pim Van Der Harst; Nicholas J. Wareham; Cisca Wijmenga; Tien Yin Wong; Myriam Fornage; Vilmundur Gudnason; Daniel Levy; Walter Palmas; Paul M. Ridker; Jerome I. Rotter; Cornelia M. Van Duijn; Jacqueline C.M. Witteman; Aravinda Chakravarti; Dabeeru C. Rao

doi:10.1016/j.ajhg.2014.05.010

Gene-age interactions in blood pressure regulation: A large-scale investigation with the CHARGE, global BPgen, and ICBP consortia

Jeannette Simino, Gang Shi, Joshua C. Bis, Daniel I. Chasman, Georg B. Ehret, Xiangjun Gu, Xiuqing Guo, Shih Jen Hwang, Eric Sijbrands, Albert V. Smith, Germaine C. Verwoert, Jennifer L. Bragg-Gresham, Gemma Cadby, Peng Chen, Ching Yu Cheng, Tanguy Corre, Rudolf A. De Boer, Anuj Goel, Toby Johnson, Chiea Chuen KhorCarla Lluís-Ganella, Jian'An Luan, Leo Pekka Lyytikäinen, Ilja M. Nolte, Xueling Sim, Siim Sõber, Peter J. Van Der Most, Niek Verweij, Jing Hua Zhao, Najaf Amin, Eric Boerwinkle, Claude Bouchard, Abbas Dehghan, Gudny Eiriksdottir, Roberto Elosua, Oscar H. Franco, Christian Gieger, Tamara B. Harris, Serge Hercberg, Albert Hofman, Alan L. James, Andrew D. Johnson, Mika Kähönen, Kay Tee Khaw, Zoltan Kutalik, Martin G. Larson, Lenore J. Launer, Guo Li, Jianjun Liu, Kiang Liu, Alanna C. Morrison, Gerjan Navis, Rick Twee Hee Ong, George J. Papanicolau, Brenda W. Penninx, Bruce M. Psaty, Leslie J. Raffel, Olli T. Raitakari, Kenneth Rice, Fernando Rivadeneira, Lynda M. Rose, Serena Sanna, Robert A. Scott, David S. Siscovick, Ronald P. Stolk, Andre G. Uitterlinden, Dhananjay Vaidya, Melanie M. Van Der Klauw, Ramachandran S. Vasan, Eranga Nishanthie Vithana, Uwe Völker, Henry Völzke, Hugh Watkins, Terri L. Young, Tin Aung, Murielle Bochud, Martin Farrall, Catharina A. Hartman, Maris Laan, Edward G. Lakatta, Terho Lehtimäki, Ruth J.F. Loos, Gavin Lucas, Pierre Meneton, Lyle J. Palmer, Rainer Rettig, Harold Snieder, E. Shyong Tai, Yik Ying Teo, Pim Van Der Harst, Nicholas J. Wareham, Cisca Wijmenga, Tien Yin Wong, Myriam Fornage, Vilmundur Gudnason, Daniel Levy, Walter Palmas, Paul M. Ridker, Jerome I. Rotter, Cornelia M. Van Duijn, Jacqueline C.M. Witteman, Aravinda Chakravarti, Dabeeru C. Rao

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Abstract

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p≤ 5 10) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 10) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

Original language	English
Pages (from-to)	24-38
Number of pages	15
Journal	American journal of human genetics
Volume	95
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2014.05.010
State	Published - Jul 3 2014

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10.1016/j.ajhg.2014.05.010

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Simino, J., Shi, G., Bis, J. C., Chasman, D. I., Ehret, G. B., Gu, X., Guo, X., Hwang, S. J., Sijbrands, E., Smith, A. V., Verwoert, G. C., Bragg-Gresham, J. L., Cadby, G., Chen, P., Cheng, C. Y., Corre, T., De Boer, R. A., Goel, A., Johnson, T., ... Rao, D. C. (2014). Gene-age interactions in blood pressure regulation: A large-scale investigation with the CHARGE, global BPgen, and ICBP consortia. American journal of human genetics, 95(1), 24-38. https://doi.org/10.1016/j.ajhg.2014.05.010

@article{bbbbfd80ffb14bf682583c7d32c22d29,

title = "Gene-age interactions in blood pressure regulation: A large-scale investigation with the CHARGE, global BPgen, and ICBP consortia",

abstract = "Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p≤ 5 10) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 10) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.",

author = "Jeannette Simino and Gang Shi and Bis, {Joshua C.} and Chasman, {Daniel I.} and Ehret, {Georg B.} and Xiangjun Gu and Xiuqing Guo and Hwang, {Shih Jen} and Eric Sijbrands and Smith, {Albert V.} and Verwoert, {Germaine C.} and Bragg-Gresham, {Jennifer L.} and Gemma Cadby and Peng Chen and Cheng, {Ching Yu} and Tanguy Corre and {De Boer}, {Rudolf A.} and Anuj Goel and Toby Johnson and Khor, {Chiea Chuen} and Carla Llu{\'i}s-Ganella and Jian'An Luan and Lyytik{\"a}inen, {Leo Pekka} and Nolte, {Ilja M.} and Xueling Sim and Siim S{\~o}ber and {Van Der Most}, {Peter J.} and Niek Verweij and Zhao, {Jing Hua} and Najaf Amin and Eric Boerwinkle and Claude Bouchard and Abbas Dehghan and Gudny Eiriksdottir and Roberto Elosua and Franco, {Oscar H.} and Christian Gieger and Harris, {Tamara B.} and Serge Hercberg and Albert Hofman and James, {Alan L.} and Johnson, {Andrew D.} and Mika K{\"a}h{\"o}nen and Khaw, {Kay Tee} and Zoltan Kutalik and Larson, {Martin G.} and Launer, {Lenore J.} and Guo Li and Jianjun Liu and Kiang Liu and Morrison, {Alanna C.} and Gerjan Navis and Ong, {Rick Twee Hee} and Papanicolau, {George J.} and Penninx, {Brenda W.} and Psaty, {Bruce M.} and Raffel, {Leslie J.} and Raitakari, {Olli T.} and Kenneth Rice and Fernando Rivadeneira and Rose, {Lynda M.} and Serena Sanna and Scott, {Robert A.} and Siscovick, {David S.} and Stolk, {Ronald P.} and Uitterlinden, {Andre G.} and Dhananjay Vaidya and {Van Der Klauw}, {Melanie M.} and Vasan, {Ramachandran S.} and Vithana, {Eranga Nishanthie} and Uwe V{\"o}lker and Henry V{\"o}lzke and Hugh Watkins and Young, {Terri L.} and Tin Aung and Murielle Bochud and Martin Farrall and Hartman, {Catharina A.} and Maris Laan and Lakatta, {Edward G.} and Terho Lehtim{\"a}ki and Loos, {Ruth J.F.} and Gavin Lucas and Pierre Meneton and Palmer, {Lyle J.} and Rainer Rettig and Harold Snieder and Tai, {E. Shyong} and Teo, {Yik Ying} and {Van Der Harst}, Pim and Wareham, {Nicholas J.} and Cisca Wijmenga and Wong, {Tien Yin} and Myriam Fornage and Vilmundur Gudnason and Daniel Levy and Walter Palmas and Ridker, {Paul M.} and Rotter, {Jerome I.} and {Van Duijn}, {Cornelia M.} and Witteman, {Jacqueline C.M.} and Aravinda Chakravarti and Rao, {Dabeeru C.}",

note = "Funding Information: B.M.P. served on a data and safety monitoring board for a clinical trial (Zoll LifeCor) and a steering committee for the Yale Open Data Access Project funded by Medtronic. P.M.R. received a grant from Amgen (>$10,000) for genotyping the WGHS. A.C. is on the Science Advisory Board of Affymetrix and Biogen Idec. ",

year = "2014",

month = jul,

day = "3",

doi = "10.1016/j.ajhg.2014.05.010",

language = "English",

volume = "95",

pages = "24--38",

journal = "American journal of human genetics",

issn = "0002-9297",

number = "1",

}

Simino, J, Shi, G, Bis, JC, Chasman, DI, Ehret, GB, Gu, X, Guo, X, Hwang, SJ, Sijbrands, E, Smith, AV, Verwoert, GC, Bragg-Gresham, JL, Cadby, G, Chen, P, Cheng, CY, Corre, T, De Boer, RA, Goel, A, Johnson, T, Khor, CC, Lluís-Ganella, C, Luan, JA, Lyytikäinen, LP, Nolte, IM, Sim, X, Sõber, S, Van Der Most, PJ, Verweij, N, Zhao, JH, Amin, N, Boerwinkle, E, Bouchard, C, Dehghan, A, Eiriksdottir, G, Elosua, R, Franco, OH, Gieger, C, Harris, TB, Hercberg, S, Hofman, A, James, AL, Johnson, AD, Kähönen, M, Khaw, KT, Kutalik, Z, Larson, MG, Launer, LJ, Li, G, Liu, J, Liu, K, Morrison, AC, Navis, G, Ong, RTH, Papanicolau, GJ, Penninx, BW, Psaty, BM, Raffel, LJ, Raitakari, OT, Rice, K, Rivadeneira, F, Rose, LM, Sanna, S, Scott, RA, Siscovick, DS, Stolk, RP, Uitterlinden, AG, Vaidya, D, Van Der Klauw, MM, Vasan, RS, Vithana, EN, Völker, U, Völzke, H, Watkins, H, Young, TL, Aung, T, Bochud, M, Farrall, M, Hartman, CA, Laan, M, Lakatta, EG, Lehtimäki, T, Loos, RJF, Lucas, G, Meneton, P, Palmer, LJ, Rettig, R, Snieder, H, Tai, ES, Teo, YY, Van Der Harst, P, Wareham, NJ, Wijmenga, C, Wong, TY, Fornage, M, Gudnason, V, Levy, D, Palmas, W, Ridker, PM, Rotter, JI, Van Duijn, CM, Witteman, JCM, Chakravarti, A & Rao, DC 2014, 'Gene-age interactions in blood pressure regulation: A large-scale investigation with the CHARGE, global BPgen, and ICBP consortia', American journal of human genetics, vol. 95, no. 1, pp. 24-38. https://doi.org/10.1016/j.ajhg.2014.05.010

TY - JOUR

T1 - Gene-age interactions in blood pressure regulation

T2 - A large-scale investigation with the CHARGE, global BPgen, and ICBP consortia

AU - Simino, Jeannette

AU - Shi, Gang

AU - Bis, Joshua C.

AU - Chasman, Daniel I.

AU - Ehret, Georg B.

AU - Gu, Xiangjun

AU - Guo, Xiuqing

AU - Hwang, Shih Jen

AU - Sijbrands, Eric

AU - Smith, Albert V.

AU - Verwoert, Germaine C.

AU - Bragg-Gresham, Jennifer L.

AU - Cadby, Gemma

AU - Chen, Peng

AU - Cheng, Ching Yu

AU - Corre, Tanguy

AU - De Boer, Rudolf A.

AU - Goel, Anuj

AU - Johnson, Toby

AU - Khor, Chiea Chuen

AU - Lluís-Ganella, Carla

AU - Luan, Jian'An

AU - Lyytikäinen, Leo Pekka

AU - Nolte, Ilja M.

AU - Sim, Xueling

AU - Sõber, Siim

AU - Van Der Most, Peter J.

AU - Verweij, Niek

AU - Zhao, Jing Hua

AU - Amin, Najaf

AU - Boerwinkle, Eric

AU - Bouchard, Claude

AU - Dehghan, Abbas

AU - Eiriksdottir, Gudny

AU - Elosua, Roberto

AU - Franco, Oscar H.

AU - Gieger, Christian

AU - Harris, Tamara B.

AU - Hercberg, Serge

AU - Hofman, Albert

AU - James, Alan L.

AU - Johnson, Andrew D.

AU - Kähönen, Mika

AU - Khaw, Kay Tee

AU - Kutalik, Zoltan

AU - Larson, Martin G.

AU - Launer, Lenore J.

AU - Li, Guo

AU - Liu, Jianjun

AU - Liu, Kiang

AU - Morrison, Alanna C.

AU - Navis, Gerjan

AU - Ong, Rick Twee Hee

AU - Papanicolau, George J.

AU - Penninx, Brenda W.

AU - Psaty, Bruce M.

AU - Raffel, Leslie J.

AU - Raitakari, Olli T.

AU - Rice, Kenneth

AU - Rivadeneira, Fernando

AU - Rose, Lynda M.

AU - Sanna, Serena

AU - Scott, Robert A.

AU - Siscovick, David S.

AU - Stolk, Ronald P.

AU - Uitterlinden, Andre G.

AU - Vaidya, Dhananjay

AU - Van Der Klauw, Melanie M.

AU - Vasan, Ramachandran S.

AU - Vithana, Eranga Nishanthie

AU - Völker, Uwe

AU - Völzke, Henry

AU - Watkins, Hugh

AU - Young, Terri L.

AU - Aung, Tin

AU - Bochud, Murielle

AU - Farrall, Martin

AU - Hartman, Catharina A.

AU - Laan, Maris

AU - Lakatta, Edward G.

AU - Lehtimäki, Terho

AU - Loos, Ruth J.F.

AU - Lucas, Gavin

AU - Meneton, Pierre

AU - Palmer, Lyle J.

AU - Rettig, Rainer

AU - Snieder, Harold

AU - Tai, E. Shyong

AU - Teo, Yik Ying

AU - Van Der Harst, Pim

AU - Wareham, Nicholas J.

AU - Wijmenga, Cisca

AU - Wong, Tien Yin

AU - Fornage, Myriam

AU - Gudnason, Vilmundur

AU - Levy, Daniel

AU - Palmas, Walter

AU - Ridker, Paul M.

AU - Rotter, Jerome I.

AU - Van Duijn, Cornelia M.

AU - Witteman, Jacqueline C.M.

AU - Chakravarti, Aravinda

AU - Rao, Dabeeru C.

N1 - Funding Information: B.M.P. served on a data and safety monitoring board for a clinical trial (Zoll LifeCor) and a steering committee for the Yale Open Data Access Project funded by Medtronic. P.M.R. received a grant from Amgen (>$10,000) for genotyping the WGHS. A.C. is on the Science Advisory Board of Affymetrix and Biogen Idec.

PY - 2014/7/3

Y1 - 2014/7/3

N2 - Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p≤ 5 10) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 10) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

AB - Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p≤ 5 10) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 10) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

UR - http://www.scopus.com/inward/record.url?scp=84904067016&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2014.05.010

DO - 10.1016/j.ajhg.2014.05.010

M3 - Article

C2 - 24954895

AN - SCOPUS:84904067016

SN - 0002-9297

VL - 95

SP - 24

EP - 38

JO - American journal of human genetics

JF - American journal of human genetics

IS - 1

ER -

Gene-age interactions in blood pressure regulation: A large-scale investigation with the CHARGE, global BPgen, and ICBP consortia

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