Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10−8) for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4) and multiple-trait analyses identified one novel locus (FRMD3) for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

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Published in PLOS Genetics, v. 13, 5, e1006728, p. 1-22.

This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Due to the large number of authors, only the first 30 and the authors affiliated with the University of Kentucky are listed in the author section above. For the complete list of authors, please download this article.

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The work was supported by the National Institutes of Health, the National Heart, Lung and Blood Institute R21HL123677 (NF) and the National Human Genome Research Institute grant HG003054 (XZ). JLi is supported by HL007567-31 (T32) from the National Heart, Lung and Blood Institute. MAN is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA.

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Study-specific phenotypes and genotypes are available from dbGaP (ARIC: phs000280.v1.p1, CHS: phs000287.v1.p1, WHI: phs000200.v1.p1, MESA: phs000283.v1.p1, Cleveland Family Study: phs000284.v1.p1, CARDIA: phs000285.v3.p). Discovery meta-analyses results for this study and readme file related to meta-analyses are available in GRASP and can be accessed from http://apps.nhlbi.nih.gov/GRASP/.

journal.pgen.1006728.s001.pdf (332 kB)
S1 Fig. Quantile-quantile plots for both individual traits and CPASSOC analysis in discovery stage.

journal.pgen.1006728.s002.pdf (527 kB)
S2 Fig. Manhattan plots of single trait and CPASSOC analyses at the discovery stage.

journal.pgen.1006728.s003.pdf (510 kB)
S3 Fig. Regional interrogation of the HOXA/EVX1, ULK4 and PLEKHG1.

journal.pgen.1006728.s004.pdf (1232 kB)
S4 Fig. Discovery stage results and linkage disequilibrium maps of the candidate regions.

journal.pgen.1006728.s005.pdf (146 kB)
S5 Fig. Enrichment for functional annotations of variants in 11 replicated loci reaching genome-wide significance.

journal.pgen.1006728.s006.pdf (22 kB)
S1 Table. Descriptive characteristics of the discovery studies.

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S2 Table. Genotyping, pre-imputation quality control, imputation and analysis methods in the participating studies.

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S3 Table. Genomic inflation factors by study and analysis.

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S4 Table. Conditional analysis of SNPs with P < 1.0 × 10−6 in discovery stage for SBP, DBP, PP, HTN or CPASSOC analysis.

journal.pgen.1006728.s010.pdf (75 kB)
S5 Table. 72 Independent SNPs with P < 1.0 × 10−6 in discovery stage for SBP, DBP, PP, HTN or CPASSOC analysis.

journal.pgen.1006728.s011.pdf (167 kB)
S6 Table. Trans-ethnic replication of 72 independent SNPs with P < 1.0 × 10−6 in discovery stage for SBP, DBP, PP, HTN or CPASSOC.

journal.pgen.1006728.s012.pdf (9 kB)
S7 Table. Summary of iHS signals in significant loci with frequency differences across ancestry populations.

journal.pgen.1006728.s013.pdf (27 kB)
S8 Table. MAGENTA analysis.

journal.pgen.1006728.s014.pdf (19 kB)
S9 Table. eQTL analysis of significant SNPs in tissues.

journal.pgen.1006728.s015.pdf (57 kB)
S10 Table. Primes for mouse expression experiments.

journal.pgen.1006728.s016.docx (112 kB)
S1 Note. Single-trait and multi-trait genome wide association analyses identify novel loci for blood pressure in African-ancestry populations.