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

J Simino; G Shi; JC Bis; DI Chasman; GB Ehret; XJ Gu; XQ Guo; SJ Hwang; E.J.G. Sijbrands; AV Smith; Germaine Verwoert; JL Bragg-Gresham; G Cadby; P Chen; CY (Ching-Yu) Cheng; TG Corre; RA de Boer; A Goel; T Johnson; CC Khor; C Lluis-Ganella; J Luan; LP Lyytikainen; IM (Ilja) Nolte; XL Sim; S Sober; PJ van der Most; N (Niek) Verweij; JH Zhao; Najaf Amin; E Boerwinkle; C Bouchard; Abbas Dehghan; G Eiriksdottir; R Elosua; OH Franco Duran; C Gieger; TB Harris; S Hercberg; Bert Hofman; AL James; AD Johnson; M Kahonen; KT Khaw; Z Kutalik; MG Larson; LJ (Lenore) Launer; G Li; JJ Liu; K Liu; AC Morrison; G Navis; RTH Ong; GJ Papanicolau; BW Penninx; BM Psaty; LJ Raffel; OT Raitakari; K Rice; Fernando Rivadeneira; LM Rose; S Sanna; RA Scott; DS Siscovick; RP (Ronald) Stolk; André Uitterlinden; D Vaidya; MM (Melanie) van der Klauw; RS Vasan; EN Vithana; U Volker; H Volzke; H Watkins; TL Young; T Aung; M Bochud; M Farrall; CA Hartman; M Laan; EG Lakatta; T Lehtimaki; RJF Loos; G Lucas; P Meneton; LJ Palmer; R Rettig; H Snieder; ES Tai; YY Teo; P van der Harst; NJ Wareham; C Wijmenga; TY (Tien Yin) Wong; M Fornage; V Gudnason; D Levy; W Palmas; PM Ridker; JI Rotter; Cornelia Duijn; JCM Witteman; A Chakravarti; DC 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, JC Bis, DI Chasman, GB Ehret, XJ Gu, XQ Guo, SJ Hwang, E.J.G. Sijbrands, AV Smith, Germaine Verwoert, JL Bragg-Gresham, G Cadby, P Chen, CY (Ching-Yu) Cheng, TG Corre, RA de Boer, A Goel, T Johnson, CC KhorC Lluis-Ganella, J Luan, LP Lyytikainen, IM (Ilja) Nolte, XL Sim, S Sober, PJ van der Most, N (Niek) Verweij, JH Zhao, Najaf Amin, E Boerwinkle, C Bouchard, Abbas Dehghan, G Eiriksdottir, R Elosua, OH Franco Duran, C Gieger, TB Harris, S Hercberg, Bert Hofman, AL James, AD Johnson, M Kahonen, KT Khaw, Z Kutalik, MG Larson, LJ (Lenore) Launer, G Li, JJ Liu, K Liu, AC Morrison, G Navis, RTH Ong, GJ Papanicolau, BW Penninx, BM Psaty, LJ Raffel, OT Raitakari, K Rice, Fernando Rivadeneira, LM Rose, S Sanna, RA Scott, DS Siscovick, RP (Ronald) Stolk, André Uitterlinden, D Vaidya, MM (Melanie) van der Klauw, RS Vasan, EN Vithana, U Volker, H Volzke, H Watkins, TL Young, T Aung, M Bochud, M Farrall, CA Hartman, M Laan, EG Lakatta, T Lehtimaki, RJF Loos, G Lucas, P Meneton, LJ Palmer, R Rettig, H Snieder, ES Tai, YY Teo, P van der Harst, NJ Wareham, C Wijmenga, TY (Tien Yin) Wong, M Fornage, V Gudnason, D Levy, W Palmas, PM Ridker, JI Rotter, Cornelia Duijn, JCM Witteman, A Chakravarti, DC Rao

Research output: Contribution to journal › Article › Academic › peer-review

95 Citations (Scopus)

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 x 10(-8)) 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 x 10(-4)) 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	Undefined/Unknown
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
Publication status	Published - 2014

Research programs

EMC COEUR-09
EMC MM-01-39-09-A
EMC NIHES-01-64-02

Access to Document

10.1016/j.ajhg.2014.05.010

Cite this

Simino, J., Shi, G., Bis, JC., Chasman, DI., Ehret, GB., Gu, XJ., Guo, XQ., Hwang, SJ., Sijbrands, E. J. G., Smith, AV., Verwoert, G., Bragg-Gresham, JL., Cadby, G., Chen, P., Cheng, CY., Corre, TG., de Boer, RA., Goel, A., Johnson, T., ... 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, 95(1), 24-38. https://doi.org/10.1016/j.ajhg.2014.05.010

@article{f10e7d017f524876b78deb7cf86f594e,

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 x 10(-8)) 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 x 10(-4)) 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 = "J Simino and G Shi and JC Bis and DI Chasman and GB Ehret and XJ Gu and XQ Guo and SJ Hwang and E.J.G. Sijbrands and AV Smith and Germaine Verwoert and JL Bragg-Gresham and G Cadby and P Chen and Cheng, {CY (Ching-Yu)} and TG Corre and {de Boer}, RA and A Goel and T Johnson and CC Khor and C Lluis-Ganella and J Luan and LP Lyytikainen and Nolte, {IM (Ilja)} and XL Sim and S Sober and {van der Most}, PJ and Verweij, {N (Niek)} and JH Zhao and Najaf Amin and E Boerwinkle and C Bouchard and Abbas Dehghan and G Eiriksdottir and R Elosua and {Franco Duran}, OH and C Gieger and TB Harris and S Hercberg and Bert Hofman and AL James and AD Johnson and M Kahonen and KT Khaw and Z Kutalik and MG Larson and Launer, {LJ (Lenore)} and G Li and JJ Liu and K Liu and AC Morrison and G Navis and RTH Ong and GJ Papanicolau and BW Penninx and BM Psaty and LJ Raffel and OT Raitakari and K Rice and Fernando Rivadeneira and LM Rose and S Sanna and RA Scott and DS Siscovick and Stolk, {RP (Ronald)} and Andr{\'e} Uitterlinden and D Vaidya and {van der Klauw}, {MM (Melanie)} and RS Vasan and EN Vithana and U Volker and H Volzke and H Watkins and TL Young and T Aung and M Bochud and M Farrall and CA Hartman and M Laan and EG Lakatta and T Lehtimaki and RJF Loos and G Lucas and P Meneton and LJ Palmer and R Rettig and H Snieder and ES Tai and YY Teo and {van der Harst}, P and NJ Wareham and C Wijmenga and Wong, {TY (Tien Yin)} and M Fornage and V Gudnason and D Levy and W Palmas and PM Ridker and JI Rotter and Cornelia Duijn and JCM Witteman and A Chakravarti and DC Rao",

year = "2014",

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

language = "Undefined/Unknown",

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, EJG, Smith, AV, Verwoert, G, 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 Duran, OH, Gieger, C, Harris, TB, Hercberg, S, Hofman, B, 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, A, 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, Duijn, C, 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: A Large-Scale Investigation with the CHARGE, Global BPgen, and ICBP Consortia

AU - Simino, J

AU - Shi, G

AU - Bis, JC

AU - Chasman, DI

AU - Ehret, GB

AU - Gu, XJ

AU - Guo, XQ

AU - Hwang, SJ

AU - Sijbrands, E.J.G.

AU - Smith, AV

AU - Verwoert, Germaine

AU - Bragg-Gresham, JL

AU - Cadby, G

AU - Chen, P

AU - Cheng, CY (Ching-Yu)

AU - Corre, TG

AU - de Boer, RA

AU - Goel, A

AU - Johnson, T

AU - Khor, CC

AU - Lluis-Ganella, C

AU - Luan, J

AU - Lyytikainen, LP

AU - Nolte, IM (Ilja)

AU - Sim, XL

AU - Sober, S

AU - van der Most, PJ

AU - Verweij, N (Niek)

AU - Zhao, JH

AU - Amin, Najaf

AU - Boerwinkle, E

AU - Bouchard, C

AU - Dehghan, Abbas

AU - Eiriksdottir, G

AU - Elosua, R

AU - Franco Duran, OH

AU - Gieger, C

AU - Harris, TB

AU - Hercberg, S

AU - Hofman, Bert

AU - James, AL

AU - Johnson, AD

AU - Kahonen, M

AU - Khaw, KT

AU - Kutalik, Z

AU - Larson, MG

AU - Launer, LJ (Lenore)

AU - Li, G

AU - Liu, JJ

AU - Liu, K

AU - Morrison, AC

AU - Navis, G

AU - Ong, RTH

AU - Papanicolau, GJ

AU - Penninx, BW

AU - Psaty, BM

AU - Raffel, LJ

AU - Raitakari, OT

AU - Rice, K

AU - Rivadeneira, Fernando

AU - Rose, LM

AU - Sanna, S

AU - Scott, RA

AU - Siscovick, DS

AU - Stolk, RP (Ronald)

AU - Uitterlinden, André

AU - Vaidya, D

AU - van der Klauw, MM (Melanie)

AU - Vasan, RS

AU - Vithana, EN

AU - Volker, U

AU - Volzke, H

AU - Watkins, H

AU - Young, TL

AU - Aung, T

AU - Bochud, M

AU - Farrall, M

AU - Hartman, CA

AU - Laan, M

AU - Lakatta, EG

AU - Lehtimaki, T

AU - Loos, RJF

AU - Lucas, G

AU - Meneton, P

AU - Palmer, LJ

AU - Rettig, R

AU - Snieder, H

AU - Tai, ES

AU - Teo, YY

AU - van der Harst, P

AU - Wareham, NJ

AU - Wijmenga, C

AU - Wong, TY (Tien Yin)

AU - Fornage, M

AU - Gudnason, V

AU - Levy, D

AU - Palmas, W

AU - Ridker, PM

AU - Rotter, JI

AU - Duijn, Cornelia

AU - Witteman, JCM

AU - Chakravarti, A

AU - Rao, DC

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 x 10(-8)) 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 x 10(-4)) 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 x 10(-8)) 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 x 10(-4)) 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.

U2 - 10.1016/j.ajhg.2014.05.010

DO - 10.1016/j.ajhg.2014.05.010

M3 - Article

C2 - 24954895

SN - 0002-9297

VL - 95

SP - 24

EP - 38

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 1

ER -