| Literature DB >> 24954895 |
Jeannette Simino1, Gang Shi2, Joshua C Bis3, Daniel I Chasman4, Georg B Ehret5, Xiangjun Gu6, Xiuqing Guo7, Shih-Jen Hwang8, Eric Sijbrands9, Albert V Smith10, Germaine C Verwoert11, Jennifer L Bragg-Gresham12, Gemma Cadby13, Peng Chen14, Ching-Yu Cheng15, Tanguy Corre16, Rudolf A de Boer17, Anuj Goel18, Toby Johnson19, Chiea-Chuen Khor20, Carla Lluís-Ganella21, Jian'an Luan22, Leo-Pekka Lyytikäinen23, Ilja M Nolte24, Xueling Sim25, Siim Sõber26, Peter J van der Most24, Niek Verweij17, Jing Hua Zhao22, Najaf Amin27, Eric Boerwinkle28, Claude Bouchard29, Abbas Dehghan27, Gudny Eiriksdottir30, Roberto Elosua31, Oscar H Franco27, Christian Gieger32, Tamara B Harris33, Serge Hercberg34, Albert Hofman27, Alan L James35, Andrew D Johnson36, Mika Kähönen37, Kay-Tee Khaw38, Zoltan Kutalik16, Martin G Larson39, Lenore J Launer33, Guo Li3, Jianjun Liu40, Kiang Liu41, Alanna C Morrison28, Gerjan Navis42, Rick Twee-Hee Ong14, George J Papanicolau43, Brenda W Penninx44, Bruce M Psaty45, Leslie J Raffel46, Olli T Raitakari47, Kenneth Rice48, Fernando Rivadeneira11, Lynda M Rose49, Serena Sanna50, Robert A Scott22, David S Siscovick51, Ronald P Stolk24, Andre G Uitterlinden52, Dhananjay Vaidya53, Melanie M van der Klauw54, Ramachandran S Vasan55, Eranga Nishanthie Vithana56, Uwe Völker57, Henry Völzke58, Hugh Watkins18, Terri L Young59, Tin Aung60, Murielle Bochud61, Martin Farrall18, Catharina A Hartman62, Maris Laan26, Edward G Lakatta63, Terho Lehtimäki23, Ruth J F Loos64, Gavin Lucas21, Pierre Meneton65, Lyle J Palmer66, Rainer Rettig67, Harold Snieder24, E Shyong Tai68, Yik-Ying Teo69, Pim van der Harst70, Nicholas J Wareham22, Cisca Wijmenga71, Tien Yin Wong60, Myriam Fornage72, Vilmundur Gudnason10, Daniel Levy73, Walter Palmas74, Paul M Ridker4, Jerome I Rotter7, Cornelia M van Duijn75, Jacqueline C M Witteman27, Aravinda Chakravarti76, Dabeeru C Rao77.
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(-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.Entities:
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Year: 2014 PMID： 24954895 PMCID： PMC4085636 DOI： 10.1016/j.ajhg.2014.05.010
Source DB: PubMed Journal: Am J Hum Genet ISSN： 0002-9297 Impact factor: 11.025