International Genome-Wide Association Study Consortium Identifies Novel Loci Associated With Blood Pressure in Children and Adolescents

Abstract

Background: Our aim was to identify genetic variants associated with blood pressure (BP) in childhood and adolescence.

Methods and results: Genome-wide association study data from participating European ancestry cohorts of the Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium was meta-analyzed across 3 epochs; prepuberty (4-7 years), puberty (8-12 years), and postpuberty (13-20 years). Two novel loci were identified as having genome-wide associations with systolic BP across specific age epochs: rs1563894 (ITGA11, located in active H3K27Ac mark and transcription factor chromatin immunoprecipitation and 5'-C-phosphate-G-3' methylation site) during prepuberty (P=2.86×10(-8)) and rs872256 during puberty (P=8.67×10(-9)). Several single-nucleotide polymorphism clusters were also associated with childhood BP at P<5×10(-3). Using a P value threshold of <5×10(-3), we found some overlap in variants across the different age epochs within our study and between several single-nucleotide polymorphisms in any of the 3 epochs and adult BP-related single-nucleotide polymorphisms.

Conclusions: Our results suggest that genetic determinants of BP act from childhood, develop over the lifecourse, and show some evidence of age-specific effects.

Keywords: Genome-Wide Association Study; blood pressure; children; genetic epidemiology; hypertension; prehypertension.

Figure 1

Regional association plots for significant SNP clusters –log10 (P values) are shown for all SNPs in the region, and color of circles indicates degree of LD with the most associated SNP in the region. SNPs correspond to those highlighted in bold text in Table 3. Plots shown on left represent systolic blood pressure, plots shown on right represent diastolic blood pressure. Rows represent prepubertal (A), pubertal (B), and postpubertal (C). For regional association, plots for all significant SNP clusters presented in Table 4 refer to Figures VII and VIII in the Data Supplement. LD indicates linkage disequilibrium.

Figure 2

Most significant SNP clusters resulting from the sex-combined meta-analyses genome-wide association study (GWAS). From top to bottom: forest plot, regional association plot (–log10 (P values)), linkage disequilibrium plots (LOD scores), and Manhattan plots (–log10 (P values)). Green boxed areas on Manhattan plots highlight chromosome regions illustrated in regional association plots. Letters signify the following data subsets: SBP (A) and DBP (B) for the prepubertal epoch. ALSPAC indicates The Avon Longitudinal Study of Parents and Children Bristol, UK; EAGLE< Early Genetics and Lifecourse Epidemiology; GenR, The Generation R Study Group, Rotterdam, The Netherlands; ICBP, International Consortium of Blood Pressure; INMA, Spanish INMA—Infancia y Medio Ambiente, Barcelona, Catalonia, Spain; Raine, The Western Australian Pregnancy (Raine) Cohort, Perth, Western Australia; YFS; The Cardiovascular Risk in Young Finns Study, Turku, Finland.

Figure 3

An overview of the Encyclopedia of DNA Elements functional activity (transcriptional active region, H3K27Ac active regulatory elements, DNase hypersensitivity transcription factor–binding site information from chromatin immunoprecipitation [ChIP] analysis, and CpG methylation levels) for rs1563894 (A; SBP) and rs1714524 (B; DBP) during the prepubertal epoch.