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### Study HypothesisInitial genome-wide association studies (GWAS) for hypertension, a common cardiovascular risk factor, have delivered unexpectedly few and modest associations. The authors of the International Consortium for Blood Pressure Genome-Wide Association Studies set out to identify novel genetic variants in relation to blood pressure, intermediate phenotypes, and cardiovascular disease risk. A joint effort combining data on 200 000 individuals of European descent increased the power to detect DNA variants with small effect sizes.### How Was the Hypothesis Tested?The authors used a staged approach for discovery, replication, and biological translation of their findings. At the identification stage, they performed a meta-analysis on genome-wide single nucleotide polymorphism (SNP) associations and off-treatment systolic and diastolic blood pressure measurements, as well as the dichotomous variable of hypertension, based on 29 studies (n≈70 000 individuals). In 3 resource-efficient sequential follow-up steps of de novo genotyping and SNP look-up in existing GWAS datasets, top hits were validated in >133 000 independent individuals of European descent. Sex and body mass index interaction analyses were performed for the top GWAS findings to understand potential effect modification.To identify possible causal mechanisms, top GWAS loci were looked up in diverse existing expression SNP data sets for cis -acting gene expression. In addition, neighboring nonsynonymous coding SNPs (linkage disequilibrium r 2 >0.8) were searched because amino acid sequence alterations harbor high potential to provide mechanistic insights. Furthermore, genetic loci were investigated in relation to ≈300 serum metabolites in >10 000 individuals of metabolomic and lipidomic studies. More than 6000 copy number variation-tagging SNPs were available for the correlation of structural genomic variation and blood pressure …

Common Genetic Variation of Blood Pressure Traits and Their Relation to End-Organ Damage