Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations

Liang, Jingjing; Le, Thu H.; Velez Edwards, Digna R.; Tayo, Bamidele O.; Gaulton, Kyle J.; Smith, Jennifer A.; Lu, Yingchang; Jensen, Richard A.; Chen, Guanjie; Yanek, Lisa R.; Schwander, Karen; Tajuddin, Salman M.; Sofer, Tamar; Kim, Wonji; Kayima, James; McKenzie, Colin A.; Fox, Ervin; Nalls, Michael A.; Young, J. Hunter; Sun, Yan V.; Lane, Jacqueline M.; Cechova, Sylvia; Zhou, Jie; Tang, Hua; Fornage, Myriam; Musani, Solomon K.; Wang, Heming; Lee, Juyoung; Adeyemo, Adebowale; Dreisbach, Albert W.; Forrester, Terrence; Chu, Pei-Lun; Cappola, Anne R.; Evans, Michele K.; Morrison, Alanna C.; Martin, Lisa W.; Wiggins, Kerri L.; Hui, Qin; Zhao, Wei; Jackson, Rebecca D.; Ware, Erin B.; Faul, Jessica D.; Reiner, Alex P.; Bray, Michael; Denny, Joshua C.; Mosley, Thomas H.; Palmas, Walter R.; Guo, Xiuqing; Papanicolaou, George J.; Penman, Alan D.; Polak, Joseph F.; Rice, Kenneth; Taylor, Ken D.; Boerwinkle, Eric; Bottinger, Erwin P.; Liu, Kiang; Risch, Neil; Hunt, Steven C.; Kooperberg, Charles; Zonderman, Alan B.; Laurie, Cathy C.; Becker, Diane M.; Cai, Jianwen; Loos, Ruth J. F.; Psaty, Bruce M.; Weir, David R.; Kardia, Sharon L. R.; Arnett, Donna K.; Won, Sungho; Edwards, Todd L.; Redline, Susan; Cooper, Richard; Rao, D. C.; Rotter, Jerome I.; Rotimi, Charles N.; Levy, Daniel; Chakravarti, Aravinda; Zhu, Xiaofeng; Franceschini, Nora

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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July 16, 2017