Exploring the missing heritability of blood pressure
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Description
Objectives: To identify genetic variants and genes underlying blood pressure (BP) regulation. Methods: We conducted genome-wide gene-sodium (paper 1) and gene-potassium (paper 2) interaction analyses among 1,876 participants of the Genetic Epidemiology Network of Salt Sensitivity study. In addition, we conducted genome-wide association study meta-analyses of long term average (LTA) BP phenotypes (paper 3) among 18,422 participants of the Asian Genetic Epidemiology Network consortium. Promising findings from all three analyses were replicated using large population-based multi-ethnic studies. SNPs with evidence of replication were meta-analyzed across discovery and replication studies. Results: We identified 7 novel BP loci and 2 novel variants with discovery stage P<1.00×10-4, replication P<0.05, and joint P<5.00×10-8. These findings include 4 loci which may interact with sodium, 3 loci and 1 variant that may interact with potassium to influence BP, and 1 variant identified by examining LTA BP. SNP-sodium interactions on diastolic BP (DBP) and mean arterial pressure (MAP) were identified for CASP5 variants rs7108444 (P= 4.96×10-8) and rs4121642 (P=4.43×10-8), respectively. CASP4 variant rs1944900 interacted with sodium to influence both systolic BP (SBP) (P= 1.57×10-10) and MAP (P= 2.33×10-10). LOC105377436 variant rs2404316 interacted with sodium to influence pulse pressure (PP) (P=3.98×10-8), while LOC105375753 variant rs11985141 interacted with sodium to influence SBP (P=1.20×10-8). Abstract iii SNP-potassium interactions on DBP were identified for LINC00336 variant rs13195171 (P=3.61×10-9) and C6orf165 variant rs9450682 (P=4.41×10-9). Variant rs9450682 also interacted with potassium on MAP (P=1.31×10-8). Associations between LTA variant rs3093542 and DBP (P=9.85×10-10) and CACNA1E variant rs12139675 and PP (P=9.38×10-10) were also identified. We identified novel ARL3 variant rs4919669 influencing LTA SBP (P=2.63×10-8) and MAP (P=2.64×10-8), and trans-ethnically replicated the association of KCNK3 variant rs1275988 with LTA SBP (P=1.27×10-4) and MAP (P=3.30×10-4) which was previously reported in a European population. Conclusion: We identified 7 novel loci and 2 novel variants that may influence BP regulation.