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Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.

TitleGene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.
Publication TypeJournal Article
Year of Publication2014
AuthorsSimino, J, Shi, G, Bis, JC, Chasman, DI, Ehret, GB, Gu, X, Guo, X, Hwang, S-J, Sijbrands, E, Smith, AV, Verwoert, GC, Bragg-Gresham, JL, Cadby, G, Chen, P, Cheng, C-Y, Corre, T, de Boer, RA, Goel, A, Johnson, T, Khor, C-C, Lluís-Ganella, C, Luan, J'an, Lyytikäinen, L-P, 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, K-T, Kutalik, Z, Larson, MG, Launer, LJ, Li, G, Liu, J, Liu, K, Morrison, AC, Navis, G, Ong, RT-H, 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, ENishanthie, 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, SE, Teo, Y-Y, van der Harst, P, Wareham, NJ, Wijmenga, C, Wong, TYin, Fornage, M, Gudnason, V, Levy, D, Palmas, W, Ridker, PM, Rotter, JI, van Duijn, CM, Witteman, JCM, Chakravarti, A, Rao, DC
Corporate/Institutional AuthorsLifeLines Cohort Study,
JournalAm J Hum Genet
Date Published2014 Jul 03
KeywordsAdolescent, Adult, Age Factors, Aged, Blood Pressure, Cohort Studies, Humans, Middle Aged, Young Adult
Abstract<p>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(-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 × 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.</p>
Alternate JournalAm. J. Hum. Genet.
PubMed ID24954895
PubMed Central IDPMC4085636
Grant ListG1000143 / / Medical Research Council / United Kingdom
UL1 TR000124 / TR / NCATS NIH HHS / United States
MC_UU_12015/1 / / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
MC_U106179471 / / Medical Research Council / United Kingdom
P30 DK063491 / DK / NIDDK NIH HHS / United States
14136 / / Cancer Research UK / United Kingdom
G0401527 / / Medical Research Council / United Kingdom
G0701863 / / Medical Research Council / United Kingdom