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

Abstract

266S ystolic and diastolic blood pressure (SBP and DBP) are complex phenotypes, with known environmental and genetic risk factors.1 Elevated SBP and DBP are associated with premature mortality 2,3 and cardiovascular diseases. 2,4-9 Clinical Perspective on p 278Recent genome-wide association studies (GWAS) have identified genetic variants associated with adult SBP and DBP and hypertension. [10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] Several of these loci are in biologically plausible candidate genes, for example, those that influence the renin-angiotensin system. 25 There are established patterns of age-related changes in BP in industrialized populations, which support a potential interaction of genetic variants with age-related changes to environmental exposures in these populations. 26,27 For genetic variants that directly modulate childhood BP, effects might change with age, might differ between developmental periods (early life, childhood, and adolescence), and might also differ to those variants that act in adulthood.Children and adolescents are rarely treated with antihypertensives, whereas from middle age onwards, an increasing proportion of adults are using such medications. 26 Consequently, it is easier to examine genetic variants that are associated with untreated SBP and DBP in children. Variation in SBP, and to 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 EarlyGenetics 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 BPrelated 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. Parmar et al Blood Pressure GWAS in Children 267a lesser extent DBP, in adolescence and early adulthood is associated with subsequent adult risk of coronary heart disease and stroke. 28,29 Understanding the risk factors, including genetic variation, that are associated with SBP and DBP through childhood and into adolescence may therefore inform an improved understanding of the life course pathogenesis of adult hypertension and cardiovascular disease...

A genome‐wide association and replication study of blood pressure in Ugandan early adolescents

“…Of the 389 SNPs (Adeyemo et al, 2009;Cho et al, 2009;Ehret et al, 2016;International Consortium for Blood Pressure Genome-Wide Association Studies et al, 2011;Evangelou et al, 2018;Fox et al, 2011;Franceschini et al, 2013;Ganesh et al, 2014Ganesh et al, , 2013Ho et al, 2011;Hoffmann et al, 2017;Johnson, Newton-Cheh, et al, 2011;Johnson, Gaunt, et al, 2011;Kato et al, 2015Kato et al, , 2011Kidambi et al, 2012;Levy et al, 2009;Li et al, 2017;Liang et al, 2017;Liu et al, 2016;Newton-Cheh, Johnson, et al, 2009;Newton-Cheh, Larson, et al, 2009;Parmar et al, 2016;Simino et al, 2014;Surendran et al, 2016;Takeuchi et al, 2010;Tragante et al, 2014;Wain et al, 2017Wain et al, , 2011Warren et al, 2017) identified for replication, 330 (85%) SNPs were included in the replication analysis. Fifty-nine SNPs that were either rare (<0.01) or poorly imputed (INFO score <0.3) in the EMaBS sample were not included in the replication analysis.…”

Inositol 1,4,5-Trisphosphate Receptors in Human Disease: A Comprehensive Update

“…An international GWAS identified ITPR1 between the novel loci associated with blood pressure in children and adolescents [110]. Finally, in the Hispanic population, ITPR1 was associated to the pathophysiology of childhood obesity [96], while ITPR3 was linked to body mass index variants conferring a high risk of extreme obesity [94].…”

A multi-ancestry genome-wide study incorporating gene–smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure

“…Variants in this gene have been identified in individuals with carotid body tumors and pheochromocytomas/paragangliomas, endocrine tumors that secrete dopamine and/or norepinephrine and can modulate BP regulation even when tumors are not clinically apparent (73,74). Variants near this locus have been marginally associated with DBP in pre-pubertal European children (75). Tyrosinase (with its related protein, TYRP1) catalyzes the first rate-limiting step in pathway in the formation of L-Dopa (76).…”