Genome-wide association analysis of blood-pressure traits in African-ancestry individuals reveals common associated genes in African and non-African populations.
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ABSTRACT:
SUBMITTER: Franceschini N
PROVIDER: S-EPMC3769920 | biostudies-literature | 2013 Sep
REPOSITORIES: biostudies-literature
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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.
Franceschini Nora N Fox Ervin E Zhang Zhaogong Z Edwards Todd L TL Nalls Michael A MA Sung Yun Ju YJ Tayo Bamidele O BO Sun Yan V YV Gottesman Omri O Adeyemo Adebawole A Johnson Andrew D AD Young J Hunter JH Rice Ken K Duan Qing Q Chen Fang F Li Yun Y Tang Hua H Fornage Myriam M Keene Keith L KL Andrews Jeanette S JS Smith Jennifer A JA Faul Jessica D JD Guangfa Zhang Z Guo Wei W Liu Yu Y Murray Sarah S SS Musani Solomon K SK Srinivasan Sathanur S Velez Edwards Digna R DR Wang Heming H Becker Lewis C LC Bovet Pascal P Bochud Murielle M Broeckel Ulrich U Burnier Michel M Carty Cara C Chasman Daniel I DI Ehret Georg G Chen Wei-Min WM Chen Guanjie G Chen Wei W Ding Jingzhong J Dreisbach Albert W AW Evans Michele K MK Guo Xiuqing X Garcia Melissa E ME Jensen Rich R Keller Margaux F MF Lettre Guillaume G Lotay Vaneet V Martin Lisa W LW Moore Jason H JH Morrison Alanna C AC Mosley Thomas H TH Ogunniyi Adesola A Palmas Walter W Papanicolaou George G Penman Alan A Polak Joseph F JF Ridker Paul M PM Salako Babatunde B Singleton Andrew B AB Shriner Daniel D Taylor Kent D KD Vasan Ramachandran R Wiggins Kerri K Williams Scott M SM Yanek Lisa R LR Zhao Wei W Zonderman Alan B AB Becker Diane M DM Berenson Gerald G Boerwinkle Eric E Bottinger Erwin E Cushman Mary M Eaton Charles C Nyberg Fredrik F Heiss Gerardo G Hirschhron Joel N JN Howard Virginia J VJ Karczewsk Konrad J KJ Lanktree Matthew B MB Liu Kiang K Liu Yongmei Y Loos Ruth R Margolis Karen K Snyder Michael M Psaty Bruce M BM Schork Nicholas J NJ Weir David R DR Rotimi Charles N CN Sale Michele M MM Harris Tamara T Kardia Sharon L R SL Hunt Steven C SC Arnett Donna D Redline Susan S Cooper Richard S RS Risch Neil J NJ Rao D C DC Rotter Jerome I JI Chakravarti Aravinda A Reiner Alex P AP Levy Daniel D Keating Brendan J BJ Zhu Xiaofeng X
American journal of human genetics 20130822 3
High blood pressure (BP) is more prevalent and contributes to more severe manifestations of cardiovascular disease (CVD) in African Americans than in any other United States ethnic group. Several small African-ancestry (AA) BP genome-wide association studies (GWASs) have been published, but their findings have failed to replicate to date. We report on a large AA BP GWAS meta-analysis that includes 29,378 individuals from 19 discovery cohorts and subsequent replication in additional samples of AA ...[more]
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Project description: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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Project description:BACKGROUND:Large genome-wide association (GWA) studies of European ancestry individuals have identified multiple genetic variants influencing iron status. Studies on the generalizability of these associations to African ancestry populations have been limited. These studies are important given interethnic differences in iron status and the disproportionate burden of iron deficiency among African ancestry populations. METHODS:We tested the associations of 20 previously identified iron status-associated single nucleotide polymorphisms (SNPs) in 628 Kenyans, 609 Tanzanians, 608 South Africans and 228 African Americans. In each study, we examined the associations present between 20 SNPs with ferritin and haemoglobin, adjusting for age, sex and CRP levels. RESULTS:In the meta analysis including all 4 African ancestry cohorts, we replicated previously reported associations with lowered haemoglobin concentrations for rs2413450 (? = -0.19, P = 0.02) and rs4820268 (? = -0.16, P = 0.04) in TMPRSS6. An association with increased ferritin concentrations was also confirmed for rs1867504 in TF (? = 1.04, P = <0.0001) in the meta analysis including the African cohorts only. CONCLUSIONS:In all meta analyses, we only replicated 4 of the 20 single nucleotide polymorphisms reported to be associated with iron status in large GWA studies of European ancestry individuals. While there is now evidence for the associations of a number of genetic variants with iron status in both European and African ancestry populations, the considerable lack of concordance highlights the importance of continued ancestry-specific studies to elucidate the genetic underpinnings of iron status in ethnically diverse populations.
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Project description:Background: Despite hypertension being highly prevalent in individuals with African-ancestry, they are under-represented in large genome-wide association studies. Inclusion of African participants is essential to better understand genetic associations with blood pressure-related traits in Africans. This systematic review critically evaluates existing studies with African-ancestry participants and identifies knowledge gaps. Methods: We followed the PRISMA protocol, HuGE Review handbook to identify literature on original research, in English, on genetic association studies for blood pressure-related traits (systolic and diastolic blood pressure, pulse and mean-arterial pressure, and hypertension) in populations with African-ancestry (January 2007 to April 2020). A narrative synthesis of the evidence was conducted. Results: Twelve studies with African-ancestry participants met the eligibility criteria, within which 10 studies met the additional genetic association data criteria (i.e., reporting only on African-ancestry participants). Across the five blood pressure-related traits, 26 genome-wide significantly associated SNPs were identified, with six SNPs linked to more than one trait, illustrating pleiotropic effects. Among the SNP associations, 12 had not previously been described in non-African studies. Discussion: The limited number of relevant studies highlights the dearth of genomic association studies on participants with African-ancestry, especially those located within Africa. Variations in study methodology, participant inclusion, adjustment for covariates (e.g., antihypertensive medication) and relatively small sample sizes make comparisons challenging, and have resulted in fewer significant associations, compared to large European studies. Regional variation in the prevalence and associated risk factors of hypertension across Africa makes a compelling argument to develop African cohorts to facilitate large genomic studies, using African-centric arrays. Data harmonisation and comparable study designs, such as described in the H3Africa CHAIR initiative, provide a good example toward achieving this goal. Other relevant information: SS and J-TB were funded by the South African National Research Foundation. MR is a South African Research Chair in Genomics and Bioinformatics of African populations hosted by the University of the Witwatersrand, funded by the Department of Science and Innovation, and administered by the NRF. This review was registered at PROSPERO (registration number: CRD42020179221) and OSF (registration DOI: 10.17605/OSF.IO/QT2HA).
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Project description:Background and purposeMetabolic traits affect ischemic stroke (IS) risk, but the degree to which this varies across different ethnic ancestries is not known. Our aim was to apply Mendelian randomization to investigate the causal effects of type 2 diabetes (T2D) liability and lipid traits on IS risk in African ancestry individuals, and to compare them to estimates obtained in European ancestry individuals.MethodsFor African ancestry individuals, genetic proxies for T2D liability and circulating lipids were obtained from a meta-analysis of the African Partnership for Chronic Disease Research study, the UK Biobank, and the Million Veteran Program (total N=77 061). Genetic association estimates for IS risk were obtained from the Consortium of Minority Population Genome-Wide Association Studies of Stroke (3734 cases and 18 317 controls). For European ancestry individuals, genetic proxies for the same metabolic traits were obtained from Million Veteran Program (lipids N=297 626, T2D N=148 726 cases, and 965 732 controls), and genetic association estimates for IS risk were obtained from the MEGASTROKE study (34 217 cases and 406 111 controls). Random-effects inverse-variance weighted Mendelian randomization was used as the main method, complemented with sensitivity analyses more robust to pleiotropy.ResultsHigher genetically proxied T2D liability, LDL-C (low-density lipoprotein cholesterol), total cholesterol and lower genetically proxied HDL-C (high-density lipoprotein cholesterol) were associated with increased risk of IS in African ancestry individuals (odds ratio per doubling the odds of T2D liability [95% CI], 1.09 [1.07-1.11]; per standard-deviation increase in LDL-C, 1.12 [1.04-1.21]; total cholesterol: 1.23 [1.06-1.43]; HDL-C, 0.93 [0.89-0.99]). There was no evidence for differences in these estimates when performing analyses in European ancestry individuals.ConclusionsOur analyses support a causal effect of T2D liability and lipid traits on IS risk in African ancestry individuals, with Mendelian randomization estimates similar to those obtained in European ancestry individuals.
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Project description:BACKGROUND:African Americans have a higher prevalence of nocturnal hypertension and nondipping blood pressure than European Americans, but the genetic contribution to these racial differences remains unclear. We assessed the association of the percentage West African genetic ancestry with nocturnal hypertension and nondipping blood pressure in 932 African Americans from the Jackson Heart Study. METHODS:Using percentage West African ancestry determined from 389 ancestry informative markers, participants were categorized into tertiles (tertile 1 [low]: <79.3%, tertile 2: ?79.3-86.3%, and tertile 3 [high]: >86.3%). Nocturnal hypertension was defined as mean nighttime (midnight-6 am) systolic (SBP)/diastolic blood pressure ?120/70 mm Hg. Nondipping blood pressure was defined as mean nighttime-to-daytime (10 am-8 pm) SBP ratio >0.90. RESULTS:Nocturnal hypertension was present in 57.9% of participants; 66.6% had nondipping blood pressure. The mean age was 59.4 years, 32.8% were male, and 56.0% were taking antihypertensive medication. The prevalence ratios (95% confidence interval) adjusted for age, sex, cardiovascular disease risk factors, and socioeconomic and psychosocial factors comparing participants with moderate and high to those with low percentage West African ancestry for nocturnal hypertension were 0.98 (0.87-1.10) and 0.95 (0.84-1.08), respectively, and for nondipping blood pressure was 0.96 (0.86-1.07) and 0.98 (0.88-1.09), respectively. CONCLUSIONS:West African ancestry was not associated with nocturnal hypertension and nondipping blood pressure among African Americans. While rare genetic variants cannot be ruled out, these data highlight the need to better understand how environmental and behavioral factors contribute to differences in nocturnal blood pressure among African Americans compared with European Americans.
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