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

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.

Genetic linkage analysis of a large family identifies FIGN as a candidate modulator of reduced penetrance in heritable pulmonary arterial hypertension

“…Among them, the aforementioned cardiorespiratory phenotypes remained on the list. Seven GWAS SNPs, located upstream from the FIGN gene, were responsible for this enrichment: rs16849225,36 37 rs1189140138 and rs144646839 for systolic blood pressure; rs1300257340 and rs1684921139 for pulse pressure measurement; rs76833157 and rs7576072 for both asthma and response to diisocyanate 41. Furthermore, one variant from a dbGAP study was associated with tunica media wall thickness of carotid arteries (rs1370493, pha003034-phs000221) 42.…”

Identification of polymorphisms in 12q24.1, ACAD10, and BRAP as novel genetic determinants of blood pressure in Japanese by exome-wide association studies

“…ALDH2 [10], HECTD4 [10], AS3MT [12], CNNM2 [6, 10, 13, 14], NT5C2 [10], and CYP17A1 [4, 10] were previously identified as loci associated with BP in previous GWASs.…”

The Role of Rare Variants in Systolic Blood Pressure: Analysis of ExomeChip Data in HyperGEN African Americans

“…Among 30,164 common variants, our strongest signal was observed at rs11711441 on chromosome 3 (with P = 1.7 ×10 −5 ). Out of 60 known BP variants identified by the 9 articles [3, 28–35], only 13 were available in our ExomeChip data. Among these 13 known variants, the smallest p-value from our analysis was observed at rs3184504 in SB2B3 (with P = 0.0029); the effect was the same direction as [3], but with lower MAF (0.057).…”