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

2014; Elsevier BV; Volume: 95; Issue: 1 Linguagem: Inglês

10.1016/j.ajhg.2014.05.010

1537-6605

Jeannette Simino, Gang Shi, Joshua C. Bis, Daniel I. Chasman, Georg Ehret, Xiangjun Gu, Xiuqing Guo, Shih-Jen Hwang, Eric J.G. 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, Guðný Eiríksdóttir, Roberto Elosúa, Oscar H. Franco, Christian Gieger, Tamara B. Harris, Serge Herçberg, Albert Hofman, Anthony James, Andrew D. Johnson, Mika Kähönen, Kay‐Tee Khaw, Zoltán Kutalik, Martin G. Larson, Lenore J. Launer, Li Guo, Jianjun Liu, Kiang Liu, Alanna C. Morrison, Gerjan Navis, Rick Twee‐Hee Ong, George J. Papanicolau, Brenda W.J.H. 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, André G. Uitterlinden, Dhananjay Vaidya, Melanie M. van der Klauw, Ramachandran S. Vasan, Eranga N. 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 Guðnason, Daniel Levy, Walter Palmas, Paul M. Ridker, Jerome I. Rotter, Cornelia M. van Duijn, Jacqueline C.M. Witteman, Aravinda Chakravarti, D. C. Rao, Behrooz Z. Alizadeh, Rudolf A. de Boer, H. Marike Boezen, Marcel Bruinenberg, Lude Franke, Pim van der Harst, Hans L. Hillege, Melanie M. van der Klauw, Gerjan Navis, Johan Ormel, Dirkje S. Postma, Judith G.M. Rosmalen, Joris P. J. Slaets, Harold Snieder, Ronald P. Stolk, Bruce H. R. Wolffenbuttel, Cisca Wijmenga,

Diet, Metabolism, and Disease

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. 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.