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Chunk #18 — Results — Functional analyses

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Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk.
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Several genes and variants with putative function are highlighted in our in silico analysis as having biological support (e.g. eQTLs or nsSNVs) and those with novelty and tractability to laboratory investigation (e.g. expression in available tissue models) are prioritized. Sentinel variants in three genes which were highly significant in the combined meta-analysis (Tables 2 and 3) are selected for experimental testing and were successfully genotyped, each for at least 100 samples. We select ADAMTS7 due to strong biological support (e.g. mouse knockout phenotype), SF3A3 due to eQTLs, and NOX4 as it contains a rare nsSNV (Supplementary Table 9) in addition to common variant associations. We use quantitative polymerase chain reaction (qPCR) to study the impact of these sentinel variants on gene expression in human VSMCs and endothelial cells (ECs) (see Online Methods). For SF3A3, the major C allele of variant rs4360494 associated with increased PP (0.278 mmHg ±0.03, P=3.7x10-16, N=307,682) is associated with SF3A3 expression in human VSMCs, although not in endothelial cells (Supplementary Fig. 13a); and the T allele of SNV rs62012628 in ADAMTS7 associated with lower DBP (0.238