New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals.
Kraja AT., Cook JP., Warren HR., Surendran P., Liu C., Evangelou E., Manning AK., Grarup N., Drenos F., Sim X., Smith AV., Amin N., Blakemore AIF., Bork-Jensen J., Brandslund I., Farmaki A-E., Fava C., Ferreira T., Herzig K-H., Giri A., Giulianini F., Grove ML., Guo X., Harris SE., Have CT., Havulinna AS., Zhang H., Jørgensen ME., Käräjämäki A., Kooperberg C., Linneberg A., Little L., Liu Y., Bonnycastle LL., Lu Y., Mägi R., Mahajan A., Malerba G., Marioni RE., Mei H., Menni C., Morrison AC., Padmanabhan S., Palmas W., Poveda A., Rauramaa R., Rayner NW., Riaz M., Rice K., Richard MA., Smith JA., Southam L., Stančáková A., Stirrups KE., Tragante V., Tuomi T., Tzoulaki I., Varga TV., Weiss S., Yiorkas AM., Young R., Zhang W., Barnes MR., Cabrera CP., Gao H., Boehnke M., Boerwinkle E., Chambers JC., Connell JM., Christensen CK., de Boer RA., Deary IJ., Dedoussis G., Deloukas P., Dominiczak AF., Dörr M., Joehanes R., Edwards TL., Esko T., Fornage M., Franceschini N., Franks PW., Gambaro G., Groop L., Hallmans G., Hansen T., Hayward C., Heikki O., Ingelsson E., Tuomilehto J., Jarvelin M-R., Kardia SLR., Karpe F., Kooner JS., Lakka TA., Langenberg C., Lind L., Loos RJF., Laakso M., McCarthy MI., Melander O., Mohlke KL., Morris AP., Palmer CNA., Pedersen O., Polasek O., Poulter NR., Province MA., Psaty BM., Ridker PM., Rotter JI., Rudan I., Salomaa V., Samani NJ., Sever PJ., Skaaby T., Stafford JM., Starr JM., van der Harst P., van der Meer P., Understanding Society Scientific Group None., van Duijn CM., Vergnaud A-C., Gudnason V., Wareham NJ., Wilson JG., Willer CJ., Witte DR., Zeggini E., Saleheen D., Butterworth AS., Danesh J., Asselbergs FW., Wain LV., Ehret GB., Chasman DI., Caulfield MJ., Elliott P., Lindgren CM., Levy D., Newton-Cheh C., Munroe PB., Howson JMM., CHARGE EXOME BP, CHD Exome+, Exome BP, GoT2D:T2DGenes Consortia, The UK Biobank Cardio-Metabolic Traits Consortium Blood Pressure Working Group† None.
BACKGROUND: Genome-wide association studies have recently identified >400 loci that harbor DNA sequence variants that influence blood pressure (BP). Our earlier studies identified and validated 56 single nucleotide variants (SNVs) associated with BP from meta-analyses of exome chip genotype data. An additional 100 variants yielded suggestive evidence of association. METHODS AND RESULTS: Here, we augment the sample with 140 886 European individuals from the UK Biobank, in whom 77 of the 100 suggestive SNVs were available for association analysis with systolic BP or diastolic BP or pulse pressure. We performed 2 meta-analyses, one in individuals of European, South Asian, African, and Hispanic descent (pan-ancestry, ≈475 000), and the other in the subset of individuals of European descent (≈423 000). Twenty-one SNVs were genome-wide significant (P<5×10-8) for BP, of which 4 are new BP loci: rs9678851 (missense, SLC4A1AP), rs7437940 (AFAP1), rs13303 (missense, STAB1), and rs1055144 (7p15.2). In addition, we identified a potentially independent novel BP-associated SNV, rs3416322 (missense, SYNPO2L) at a known locus, uncorrelated with the previously reported SNVs. Two SNVs are associated with expression levels of nearby genes, and SNVs at 3 loci are associated with other traits. One SNV with a minor allele frequency <0.01, (rs3025380 at DBH) was genome-wide significant. CONCLUSIONS: We report 4 novel loci associated with BP regulation, and 1 independent variant at an established BP locus. This analysis highlights several candidate genes with variation that alter protein function or gene expression for potential follow-up.