Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia.
American journal of human genetics 2014 ; 95: 24-38.
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, Lifelines Cohort Study, Lluís-Ganella C, Luan J, 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 RT, 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 RJ, 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, and Rao DC
PubMed ID : 24954895
PMCID : PMC4085636
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.