Gene-Age Interactions in Blood Pressure Regulation: A Large-Scale Investigation with the CHARGE, Global BPgen, and ICBP Consortia

J. Simino; G. Shi; J.C. Bis; D.I. Chasman; G.B. Ehret; X.J. Gu; X.Q. Guo; S.J. Hwang; E. Sijbrands; A.V. Smith; G.C. Verwoert; J.L. Bragg-Gresham; G. Cadby; P. Chen; C.Y. Cheng; T.G. Corre; R.A. de Boer; A. Goel; T. Johnson; C.C. Khor; C. Lluis-Ganella; J. Luan; L.P. Lyytikainen; I.M. Nolte; X.L. Sim; S. Sober; P.J. van der Most; N. Verweij; J.H. Zhao; N. Amin; E. Boerwinkle; C. Bouchard; A. Dehghan; G. Eiriksdottir; R. Elosua; O.H. Franco; C. Gieger; T.B. Harris; S. Hercberg; A. Hofman; A.L. James; A.D. Johnson; M. Kahonen; K.T. Khaw; Z. Kutalik; M.G. Larson; L.J. Launer; G. Li; J.J. Liu; K. Liu; A.C. Morrison; G. Navis; R.T.H. Ong; G.J. Papanicolau; B.W. Penninx; B.M. Psaty; L.J. Raffel; O.T. Raitakari; K. Rice; F. Rivadeneira; L.M. Rose; S. Sanna; R.A. Scott; D.S. Siscovick; R.P Stolk; A. G. Uitterlinden; D. Vaidya; M.M. van der Klauw; R.S. Vasan; E.N. Vithana; U. Volker; H. Volzke; H. Watkins; T.L. Young; T. Aung; M. Bochud; M. Farrall; C.A. Hartman; M. Laan; E.G. Lakatta; T. Lehtimaki; R.J.F. Loos; G. Lucas; P. Meneton; L.J. Palmer; R. Rettig; H. Snieder; E.S. Tai; Y.Y. Teo; P. van der Harst; N.J. Wareham; C. Wijmenga; T.Y. Wong; M. Fornage; V. Gudnason; D. Levy; W. Palmas; P.M. Ridker; J.I. Rotter; C.M. van Duijn; J.C. Witteman; A. Chakravarti; D.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

J. Simino, G. Shi, J.C. Bis, D.I. Chasman, G.B. Ehret, X.J. Gu, X.Q. Guo, S.J. Hwang, E. Sijbrands, A.V. Smith, G.C. Verwoert, J.L. Bragg-Gresham, G. Cadby, P. Chen, C.Y. Cheng, T.G. Corre, R.A. de Boer, A. Goel, T. Johnson, C.C. KhorC. Lluis-Ganella, J. Luan, L.P. Lyytikainen, I.M. Nolte, X.L. Sim, S. Sober, P.J. van der Most, N. Verweij, J.H. Zhao, N. Amin, E. Boerwinkle, C. Bouchard, A. Dehghan, G. Eiriksdottir, R. Elosua, O.H. Franco, C. Gieger, T.B. Harris, S. Hercberg, A. Hofman, A.L. James, A.D. Johnson, M. Kahonen, K.T. Khaw, Z. Kutalik, M.G. Larson, L.J. Launer, G. Li, J.J. Liu, K. Liu, A.C. Morrison, G. Navis, R.T.H. Ong, G.J. Papanicolau, B.W. Penninx, B.M. Psaty, L.J. Raffel, O.T. Raitakari, K. Rice, F. Rivadeneira, L.M. Rose, S. Sanna, R.A. Scott, D.S. Siscovick, R.P Stolk, A. G. Uitterlinden, D. Vaidya, M.M. van der Klauw, R.S. Vasan, E.N. Vithana, U. Volker, H. Volzke, H. Watkins, T.L. Young, T. Aung, M. Bochud, M. Farrall, C.A. Hartman, M. Laan, E.G. Lakatta, T. Lehtimaki, R.J.F. Loos, G. Lucas, P. Meneton, L.J. Palmer, R. Rettig, H. Snieder, E.S. Tai, Y.Y. Teo, P. van der Harst, N.J. Wareham, C. Wijmenga, T.Y. Wong, M. Fornage, V. Gudnason, D. Levy, W. Palmas, P.M. Ridker, J.I. Rotter, C.M. van Duijn, J.C. Witteman, A. Chakravarti, D.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. © 2014 The American Society of Human Genetics.

Original language	English
Pages (from-to)	24-38
Journal	American Journal of Human Genetics
Volume	95
Issue number	1
DOIs	https://doi.org/10.1016/j.ajhg.2014.05.010
Publication status	Published - 2014

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Simino, J., Shi, G., Bis, J. C., Chasman, D. I., Ehret, G. B., Gu, X. J., Guo, X. Q., Hwang, S. J., Sijbrands, E., Smith, A. V., Verwoert, G. C., Bragg-Gresham, J. L., Cadby, G., Chen, P., Cheng, C. Y., Corre, T. G., 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{b5c858c675924840ad76fa582491fd21,

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. {\textcopyright} 2014 The American Society of Human Genetics.",

author = "J. Simino and G. Shi and J.C. Bis and D.I. Chasman and G.B. Ehret and X.J. Gu and X.Q. Guo and S.J. Hwang and E. Sijbrands and A.V. Smith and G.C. Verwoert and J.L. Bragg-Gresham and G. Cadby and P. Chen and C.Y. Cheng and T.G. Corre and {de Boer}, R.A. and A. Goel and T. Johnson and C.C. Khor and C. Lluis-Ganella and J. Luan and L.P. Lyytikainen and I.M. Nolte and X.L. Sim and S. Sober and {van der Most}, P.J. and N. Verweij and J.H. Zhao and N. Amin and E. Boerwinkle and C. Bouchard and A. Dehghan and G. Eiriksdottir and R. Elosua and O.H. Franco and C. Gieger and T.B. Harris and S. Hercberg and A. Hofman and A.L. James and A.D. Johnson and M. Kahonen and K.T. Khaw and Z. Kutalik and M.G. Larson and L.J. Launer and G. Li and J.J. Liu and K. Liu and A.C. Morrison and G. Navis and R.T.H. Ong and G.J. Papanicolau and B.W. Penninx and B.M. Psaty and L.J. Raffel and O.T. Raitakari and K. Rice and F. Rivadeneira and L.M. Rose and S. Sanna and R.A. Scott and D.S. Siscovick and R.P Stolk and Uitterlinden, {A. G.} and D. Vaidya and {van der Klauw}, M.M. and R.S. Vasan and E.N. Vithana and U. Volker and H. Volzke and H. Watkins and T.L. Young and T. Aung and M. Bochud and M. Farrall and C.A. Hartman and M. Laan and E.G. Lakatta and T. Lehtimaki and R.J.F. Loos and G. Lucas and P. Meneton and L.J. Palmer and R. Rettig and H. Snieder and E.S. Tai and Y.Y. Teo and {van der Harst}, P. and N.J. Wareham and C. Wijmenga and T.Y. Wong and M. Fornage and V. Gudnason and D. Levy and W. Palmas and P.M. Ridker and J.I. Rotter and {van Duijn}, C.M. and J.C. Witteman and A. Chakravarti and D.C. Rao",

year = "2014",

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

language = "English",

volume = "95",

pages = "24--38",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "1",

}

Simino, J, Shi, G, Bis, JC, Chasman, DI, Ehret, GB, Gu, XJ, Guo, XQ, Hwang, SJ, Sijbrands, E, Smith, AV, Verwoert, GC, Bragg-Gresham, JL, Cadby, G, Chen, P, Cheng, CY, Corre, TG, de Boer, RA, Goel, A, Johnson, T, Khor, CC, Lluis-Ganella, C, Luan, J, Lyytikainen, LP, Nolte, IM, Sim, XL, Sober, 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, Kahonen, M, Khaw, KT, Kutalik, Z, Larson, MG, Launer, LJ, Li, G, Liu, JJ, 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, Volker, U, Volzke, H, Watkins, H, Young, TL, Aung, T, Bochud, M, Farrall, M, Hartman, CA, Laan, M, Lakatta, EG, Lehtimaki, 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, JC, 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: A Large-Scale Investigation with the CHARGE, Global BPgen, and ICBP Consortia

AU - Simino, J.

AU - Shi, G.

AU - Bis, J.C.

AU - Chasman, D.I.

AU - Ehret, G.B.

AU - Gu, X.J.

AU - Guo, X.Q.

AU - Hwang, S.J.

AU - Sijbrands, E.

AU - Smith, A.V.

AU - Verwoert, G.C.

AU - Bragg-Gresham, J.L.

AU - Cadby, G.

AU - Chen, P.

AU - Cheng, C.Y.

AU - Corre, T.G.

AU - de Boer, R.A.

AU - Goel, A.

AU - Johnson, T.

AU - Khor, C.C.

AU - Lluis-Ganella, C.

AU - Luan, J.

AU - Lyytikainen, L.P.

AU - Nolte, I.M.

AU - Sim, X.L.

AU - Sober, S.

AU - van der Most, P.J.

AU - Verweij, N.

AU - Zhao, J.H.

AU - Amin, N.

AU - Boerwinkle, E.

AU - Bouchard, C.

AU - Dehghan, A.

AU - Eiriksdottir, G.

AU - Elosua, R.

AU - Franco, O.H.

AU - Gieger, C.

AU - Harris, T.B.

AU - Hercberg, S.

AU - Hofman, A.

AU - James, A.L.

AU - Johnson, A.D.

AU - Kahonen, M.

AU - Khaw, K.T.

AU - Kutalik, Z.

AU - Larson, M.G.

AU - Launer, L.J.

AU - Li, G.

AU - Liu, J.J.

AU - Liu, K.

AU - Morrison, A.C.

AU - Navis, G.

AU - Ong, R.T.H.

AU - Papanicolau, G.J.

AU - Penninx, B.W.

AU - Psaty, B.M.

AU - Raffel, L.J.

AU - Raitakari, O.T.

AU - Rice, K.

AU - Rivadeneira, F.

AU - Rose, L.M.

AU - Sanna, S.

AU - Scott, R.A.

AU - Siscovick, D.S.

AU - Stolk, R.P

AU - Uitterlinden, A. G.

AU - Vaidya, D.

AU - van der Klauw, M.M.

AU - Vasan, R.S.

AU - Vithana, E.N.

AU - Volker, U.

AU - Volzke, H.

AU - Watkins, H.

AU - Young, T.L.

AU - Aung, T.

AU - Bochud, M.

AU - Farrall, M.

AU - Hartman, C.A.

AU - Laan, M.

AU - Lakatta, E.G.

AU - Lehtimaki, T.

AU - Loos, R.J.F.

AU - Lucas, G.

AU - Meneton, P.

AU - Palmer, L.J.

AU - Rettig, R.

AU - Snieder, H.

AU - Tai, E.S.

AU - Teo, Y.Y.

AU - van der Harst, P.

AU - Wareham, N.J.

AU - Wijmenga, C.

AU - Wong, T.Y.

AU - Fornage, M.

AU - Gudnason, V.

AU - Levy, D.

AU - Palmas, W.

AU - Ridker, P.M.

AU - Rotter, J.I.

AU - van Duijn, C.M.

AU - Witteman, J.C.

AU - Chakravarti, A.

AU - Rao, D.C.

PY - 2014

Y1 - 2014

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. © 2014 The American Society of Human Genetics.

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. © 2014 The American Society of Human Genetics.

U2 - 10.1016/j.ajhg.2014.05.010

DO - 10.1016/j.ajhg.2014.05.010

M3 - Article

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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