Genome-wide Association Analysis of Blood-Pressure Traits in African-Ancestry Individuals Reveals Common Associated Genes in African and Non-African Populations

Franceschini, Nora; Fox, Ervin R.; Zhang, Zhaogong; Edwards, Todd L.; Nalls, Michael A.; Sung, Yun Ju; Tayo, Bamidele O.; Sun, Yan V.; Gottesman, Omri; Adeyemo, Adebowale; Johnson, Andrew D.; Young, J. Hunter; Rice, Ken; Duan, Qing; Chen, Fang; Li, Yun; Tang, Hua; Fornage, Myriam; Keene, Keith L.; Andrews, Jeanette S.; Smith, Jennifer A.; Faul, Jessica D.; Zhang, Guangfa; Guo, Wei; Yu, Li; Murray, Sarah; Musani, Solomon K.; Srinivasan, Sathanur R.; Edwards, Digna R. Velez; Wang, Heming; Becker, Lewis C.; Bovet, Pascal; Bochud, Murielle; Broeckel, Ulrich; Burnier, Michel; Carty, Cara L.; Chasman, Daniel I.; Ehret, Georg; Chen, Wei Min; Chen, Guanjie; Chan, Weng Kong; Ding, Jingzhong; Dreisbach, Albert W.; Evans, Michele K.; Guo, Xiuqing; García, Melissa; Jensen, Rich; Keller, Margaux F.; Lettre, Guillaume; Lotay, Vaneet; Martin, Lisa W.; Moore, Jason H.; Morrison, Alanna C.; Mosley, Thomas H.; Ogunniyi, Adesola; Palmas, Walter; Papanicolaou, George; Penman, Alan D.; Polak, Joseph F.; Ridker, Paul M.; Salako, Babatunde Lawal; Singleton, Andrew B.; Shriner, Daniel; Taylor, Kent D.; Vasan, Ramachandran S.; Wiggins, Kerri L.; Williams, Scott M.; Yanek, Lisa R.; Zhao, Wei; Zonderman, Alan B.; Becker, Diane M.; Berenson, Gerald S.; Boerwinkle, Eric; Böttinger, Erwin P.; Cushman, Mary; Eaton, Charles B.; Nyberg, Fredrik; Heiss, Gerardo; Hirschhron, Joel N.; Howard, Virginia J.; Karczewsk, Konrad J.; Lanktree, Matthew B.; Liu, Kiang; Liu, Yongmei; Loos, Ruth J.F.; Margolis, Karen L.; Snyder, M; Psaty, Bruce M.; Schork, Nicholas J.; Weir, David R.; Rotimi, Charles N.; Sale, Michèle M.; Harris, Tamara B.; Kardia, Sharon L.R.; Hunt, Steven C.; Arnett, Donna K.; Redline, Susan; Cooper, Richard S.; Risch, Neil; Rao, D. C.; Rotter, Jerome I.; Chakravarti, Aravinda; Reiner, Alex P.; Levy, Daniel; Keating, Brendan J.; Zhu, Xiaofeng

doi:10.1016/j.ajhg.2013.07.010

Cited by 187 publications

(198 citation statements)

References 41 publications

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“…In contrast, for a variety of complex traits studied to date, accumulating evidence suggests considerable numbers of overlap loci between ethnicities. [30][31][32][33] For these traits, a large proportion of SNPs selected based on a large European GWAS are expected to be relevant in non-European populations. Therefore, a set selected based on a large GWAS in a non-matching population is expected to harbor higher fraction of variants for the target population than a set selected on a small dataset in matching population.…”

Section: Discussionmentioning

confidence: 99%

Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative Traits in Minority Populations

Coram

Fang

Candille

et al. 2017

The American Journal of Human Genetics

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An essential component of precision medicine is the ability to predict an individual's risk of disease based on genetic and non-genetic factors. For complex traits and diseases, assessing the risk due to genetic factors is challenging because it requires knowledge of both the identity of variants that influence the trait and their corresponding allelic effects. Although the set of risk variants and their allelic effects may vary between populations, a large proportion of these variants were identified based on studies in populations of European descent. Heterogeneity in genetic architecture underlying complex traits and diseases, while broadly acknowledged, remains poorly characterized. Ignoring such heterogeneity likely reduces predictive accuracy for minority individuals. In this study, we propose an approach, called XP-BLUP, which ameliorates this ethnic disparity by combining trans-ethnic and ethnic-specific information. We build a polygenic model for complex traits that distinguishes candidate trait-relevant variants from the rest of the genome. The set of candidate variants are selected based on studies in any human population, yet the allelic effects are evaluated in a population-specific fashion. Simulation studies and real data analyses demonstrate that XP-BLUP adaptively utilizes trans-ethnic information and can substantially improve predictive accuracy in minority populations. At the same time, our study highlights the importance of the continued expansion of minority cohorts.

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Section: Discussionmentioning

confidence: 99%

Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative Traits in Minority Populations

Coram

Fang

Candille

et al. 2017

The American Journal of Human Genetics

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“…Among these 11 Rho-GEFs, GEF-H1, LARG and p190RhoGEF are RhoA-targeting GEFs that are involved in integrin-mediated mechanotransduction at focal adhesions (Lim et al, 2008;Tomar and Schlaepfer, 2009;Guilluy et al, 2011). In addition, single-nucleotide polymorphism analysis revealed that the genes encoding ARHGEF10 and PLEKHG1 are associated with atherothrombotic stroke and high blood pressure traits, respectively (Matsushita et al, 2010;Franceschini et al, 2013), suggesting that they have roles in blood vessel homeostasis and functions. However, little is known about the regulation mechanisms and functional roles of these Rho-GEFs in mechanotransduction in vascular endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Rho-guanine nucleotide exchange factors involved in cyclic stretch-induced reorientation of vascular endothelial cells

Abiko¹,

Fujiwara²,

Ohashi³

et al. 2015

Journal of Cell Science

111

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Cyclic stretch is an artificial model of mechanical force loading, which induces the reorientation of vascular endothelial cells and their stress fibers in a direction perpendicular to the stretch axis. Rho family GTPases are crucial for cyclic-stretch-induced endothelial cell reorientation; however, the mechanism underlying stretch-induced activation of Rho family GTPases is unknown. A screen of short hairpin RNAs targeting 63 Rho guanine nucleotide exchange factors (Rho-GEFs) revealed that at least 11 Rho-GEFs -Abr, alsin, ARHGEF10, Bcr, GEF-H1 (also known as ARHGEF2), LARG (also known as ARHGEF12), p190RhoGEF (also known as ARHGEF28), PLEKHG1, P-REX2, Solo (also known as ARHGEF40) and a-PIX (also known as ARHGEF6) -which specifically or broadly target RhoA, Rac1 and/or Cdc42, are involved in cyclic-stretch-induced perpendicular reorientation of endothelial cells. Overexpression of Solo induced RhoA activation and F-actin accumulation at cell-cell and cell-substrate adhesion sites. Knockdown of Solo suppressed cyclic-stretch-or tensile-force-induced RhoA activation. Moreover, knockdown of Solo significantly reduced cyclic-stretch-induced perpendicular reorientation of endothelial cells when cells were cultured at high density, but not when they were cultured at low density or pretreated with EGTA or VE-cadherin-targeting small interfering RNAs. These results suggest that Solo is involved in cellcell-adhesion-mediated mechanical signal transduction during cyclicstretch-induced endothelial cell reorientation.

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“…1,2 Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with blood pressure (BP). [3][4][5][6][7][8][9] Genetic risk scores (GRSs) based on those genetic variants identified in European populations were reported to be associated with incident hypertension and cardiovascular events. tobacco use, which affect the variability of BP.…”

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confidence: 99%

Genetic Predisposition to Higher Blood Pressure Increases Risk of Incident Hypertension and Cardiovascular Diseases in Chinese

Huang

Wang

et al. 2015

Hypertension

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Recently, GWAS in East Asian and Chinese not only replicated previously reported BP loci in European populations but also identified several East Asian-specific variants for BP, 4,12 which suggested that both shared and population-specific BP susceptibility were commonly present. Moreover, besides genetic heterogeneity, there are marked differences between Chinese and Europeans in environmental exposure factors, including weight, diet, physical activity, obesity, alcohol drinking, and Abstract-Although multiple genetic markers associated with blood pressure have been identified by genome-wide association studies, their aggregate effect on risk of incident hypertension and cardiovascular disease is uncertain, particularly among East Asian who may have different genetic and environmental exposures from Europeans. We aimed to examine the association between genetic predisposition to higher blood pressure and risk of incident hypertension and cardiovascular disease in 26 262 individuals in 2 Chinese population-based prospective cohorts. A genetic risk score was calculated based on 22 established variants for blood pressure in East Asian. We found the genetic risk score was significantly and independently associated with linear increases in blood pressure and risk of incident hypertension and cardiovascular disease (P range from 4.57×10 -3 to 3.10×10 -6 ). In analyses adjusted for traditional risk factors including blood pressure, individuals carrying most blood pressure-related risk alleles (top quintile of genetic score distribution) had 40% (95% confidence interval, 18-66) and 26% (6-45) increased risk for incident hypertension and cardiovascular disease, respectively, when compared with individuals in the bottom quintile. The genetic risk score also significantly improved discrimination for incident hypertension and cardiovascular disease and led to modest improvements in risk reclassification for cardiovascular disease (all the P<0.05). Our data indicate that genetic predisposition to higher blood pressure is an independent risk factor for blood pressure increase and incident hypertension and cardiovascular disease and provides modest incremental information to cardiovascular disease risk prediction. The potential clinical use of this panel of blood pressure-associated polymorphisms remains to be determined. (Hypertension. 2015;66:786-792.

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Genome-wide Association Analysis of Blood-Pressure Traits in African-Ancestry Individuals Reveals Common Associated Genes in African and Non-African Populations

Cited by 187 publications

References 41 publications

Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative Traits in Minority Populations

Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative Traits in Minority Populations

Rho-guanine nucleotide exchange factors involved in cyclic stretch-induced reorientation of vascular endothelial cells

Genetic Predisposition to Higher Blood Pressure Increases Risk of Incident Hypertension and Cardiovascular Diseases in Chinese

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