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Genome-Wide Association Study Meta-Analysis Reveals Transethnic Replication of Mean Arterial and Pulse Pressure Loci

Originally publishedhttps://doi.org/10.1161/HYPERTENSIONAHA.113.01148Hypertension. 2013;62:853–859

Abstract

We conducted a genome-wide association study meta-analysis of mean arterial pressure and pulse pressure among 26 600 East Asian participants (stage 1) followed by replication study of up to 28 783 participants (stage 2). For novel loci, statistical significance was determined by a P<5.0×10–8 in joint analysis of stage 1 and stage 2 data. For loci reported by the previous mean arterial and pulse pressure genome-wide association study meta-analysis in Europeans, evidence of transethnic replication was determined by consistency in effect direction and a Bonferroni-corrected P<1.4×10–3. No novel loci were identified by the current study. Five independent mean arterial pressure variants demonstrated robust evidence for transethnic replication including rs17249754 at ATP2B1 (P=7.5×10–15), rs2681492 at ATP2B1 (P=3.4×10–7), rs11191593 at NT5C2 (1.1×10–6), rs3824755 at CYP17A1 (P=1.2×10–6), and rs13149993 at FGF5 (P=2.4×10–4). Two additional variants showed suggestive evidence of transethnic replication (consistency in effect direction and P<0.05), including rs319690 at MAP4 (P=0.014) and rs1173771 at NPR3 (P=0.018). For pulse pressure, robust evidence of replication was identified for 2 independent variants, including rs17249754 at ATP2B1 (P=1.2×10–5) and rs11191593 at NT5C2 (P=1.1×10–3), with suggestive evidence of replication among an additional 2 variants including rs3824755 at CYP17A1 (P=6.1×10–3) and rs2681492 at ATP2B1 (P=9.0×10–3). Replicated variants demonstrated consistency in effect sizes between East Asian and European samples, with effect size differences ranging from 0.03 to 0.24 mm Hg for mean arterial pressure and from 0.03 to 0.21 mm Hg for pulse pressure. In conclusion, we present the first evidence of transethnic replication of several mean arterial and pulse pressure loci in an East Asian population.

Introduction

Hypertension affects ≈30% of the world’s adult population and has been identified as the leading risk factor for mortality globally.13 A common complex trait, high blood pressure (BP) is influenced by genomic and environmental factors, as well as their interactions.47 Recent genome-wide association study (GWAS) meta-analyses have made important strides in advancing hypertension genomic research through the identification of numerous novel loci for systolic BP (SBP) and diastolic BP (DBP).47 Mean arterial pressure (MAP), defined as the average pressure in the arteries, and pulse pressure (PP), a measure of large artery stiffness, represent 2 additional BP components which also predict cardiovascular disease risk and mortality.811 Despite their public health relevance and established heritability,1214 only 1 previous GWAS meta-analysis has reported genomic loci influencing these traits.15 Wain et al15 described several novel MAP and PP loci which they identified exclusively in populations of European descent. GWAS meta-analyses in distinct ethnic groups could enable the discovery of additional novel loci for MAP and PP and help to determine whether the previously reported variants are relevant to populations of non-European ancestry.

We performed the first ever GWAS meta-analysis of MAP and PP in East Asian participants to (1) identify novel loci influencing MAP and PP and (2) determine whether loci previously identified in populations of European ancestry could be replicated among a distinct ethnic group. Here, we report the results of our 2-stage study that included a meta-analysis of MAP and PP GWAS in 26 600 participants and replication study in up to 28 783 participants.

Methods

Stage 1: GWAS Meta-Analysis

The Asian Genetic Epidemiology Network (AGEN)-MAP/PP work group consists of 9 GWAS conducted in East Asian populations. Each AGEN-MAP/PP study collected ≥2 measurements of SBP and DBP in a clinical setting using methods described previously.6 If participants were taking antihypertension medications, 10 and 5 mm Hg were added to measured SBP and DBP, respectively. Mean MAP and PP were calculated for each participant from SBP and DBP values. Before GWAS, each study imputed the HapMap set of ≈2.4 million single-nucleotide polymorphisms (SNPs).1618 GWAS of MAP and PP in each study was performed using linear regression models to adjust for age, age2, sex, body mass index, and enrollment site (for multisite studies). Detailed study-specific information can be found in Table 1, the Supplementary Note in the online-only Data Supplement, and Table S1 in the online-only Data Supplement.

Table 1. Characteristics of AGEN-MAP/PP Studies

StudyNAncestryBlood Pressure Measurement (Device, Number of Measures)Age(SD), yWomen, %BMI (SD), kg/m2SBP (SD), mm HgDBP (SD), mm HgMAP (SD), mm Hg*PP (SD), mm HgHypertension, %Antihypertension Medication, %
Stage 1: AGEN-MAP/PP GWAS meta-analysis (n=26 600)
 CAGE1547JapaneseStandard mercury sphygmomanometer, 2–3/digital, 2–366.1 (8.0)42.823.5 (3.3)134.1 (20.3)76.8 (11.9)98.4 (14.5)59.2 (15.6)56.137.9
 CLHNS1787FilipinoStandard mercury sphygmomanometer, 348.4 (6.1)10024.3 (4.4)120.0 (20.5)79.8 (12.7)93.2 (14.5)40.2 (12.8)27.33.8
 GenSalt1881ChineseRandom zero sphygmomanometer, 938.7 (9.5)47.223.3 (3.2)116.9 (14.2)73.7 (10.3)88.2 (10.9)43.2 (9.5)9.80.37
 KARE8842KoreanStandard mercury sphygmomanometer, 352.2 (8.9)52.724.6 (3.1)118.7 (19.4)75.6 (12.0)90.0 (13.8)43.1 (11.8)22.310.9
 NHAPC2817ChineseOmron HEM-705 CP Blood Pressure Monitor, 358.6 (6.0)56.924.5 (3.6)143.0 (24.8)81.6 (11.7)102.0 (14.9)61.5 (18.2)55.928.7
 SiMES2538MalayRandom zero sphygmomanometer, 2-359.1 (11.1)50.526.4 (5.1)150.2 (24.8)81.2 (11.4)104.2 (10.9)69.0 (19.1)69.923.0
 SP22434ChineseRandom zero sphygmomanometer, 2-348.1 (11.2)53.522.9 (3.7)130.8 (21.3)77.6 (11.2)95.3 (13.6)53.2 (14.9)18.014.3
 Taiwan Type 2 Diabetes Study1000ChineseRandom zero sphygmomanometer, 351.2 (17.8)49.823.8 (3.5)122.6 (19.4)76.5 (11.0)91.9 (12.7)46.1 (14.4)8.96.8
 Vanderbilt3754ChineseSphygmomanometer, 2-357.1 (8.4)76.024.8 (3.5)128.7 (19.4)80.5 (10.5)96.5 (12.6)48.2 (14.4)49.022.7
Stage 2: Replication study (n=28 783)
 In silico genotyping studies (n=5584)
  Health examinee3703KoreanStandard mercury sphygmomanometer, 253.2 (8.3)55.424.0 (2.9)121.7 (14.4)77.1 (9.9)91.9 (10.7)44.7 (9.2)18.70
  SCES1881ChineseRandom zero sphygmomanometer, 358.4 (9.5)48.723.7 (3.5)140.8 (20.5)80.6 (9.9)100.7 (12.1)60.2 (16.3)56.151.8
 De novo genotyping studies (n=23 199)
  CAGE-Amagasaki5331JapaneseDigital, 2–347.8 (12.3)39.823.0 (3.2)124.3 (17.3)75.9 (11.0)92.1 (12.9)48.4 (8.5)57.923.9
  JMGP11 570JapaneseDigital cuff-oscillometric device, 256.1 (14.0)50.023.0 (3.1)131.3 (19.6)78.4 (11.6)96.0 (13.4)52.6 (13.1)41.619.2
  SMWHS3237ChineseSphygmomanometer, 2–359.3 (8.8)56.025.3 (3.6)132.6 (19.6)82.6 (10.5)100.7 (13.4)51.1 (15.0)53.021.3
  Suzhou Study3061ChineseStandard mercury sphygmomanometer, 254.2 (10.5)61.724.8 (3.6)134.2 (19.8)86.4 (10.2)70.5 (9.9)47.8 (14.3)47.227.5

AGEN indicates Asian Genetic Epidemiology Network; BP, blood pressure; CAGE, Cardio-metabolic Genome Epidemiology; CLHNS, Cebu Longitudinal Health and Nutrition Survey; DBP, diastolic blood pressure; GenSalt, Genetic Epidemiology Network of Salt-Sensitivity; GWAS, genome-wide association study; HTN, hypertension; JMGP, Japanese Millenium Genome Project; KARE, Korean Association Resource; MAP, mean arterial pressure; N, sample size; NHAPC, Nutrition and Health of Aging Population in China; PP, pulse pressure; SBP, systolic blood pressure; SCES, Singapore Chinese Eyes Study; Vanderbilt, Vanderbilt Genome-Wide Association Studies; SiMES, Singapore Malay Eye Study; SMWHS, Shanghai Men’s and Shanghai Women’s Health Studies; and SP2, Singapore Prospective Study.

*MAP is calculated as DBP+(SBP–DBP)/3 in each study.

PP is calculated as SBP–DBP in each study.

Hypertension is defined as SBP ≥140 mm Hg and DBP ≥90 mm Hg or taking antihypertension medication.

Inverse-variance weighted fixed-effect meta-analyses of MAP and PP results from the 9 GWAS were performed using METAL.19 SNPs were excluded if they had minor allele frequency <0.05, Hardy–Weinberg P<1×10−6, call rate <0.95, imputation quality score <0.5, sample size <10 000 or showed evidence of heterogeneity across studies (P for Cochrane Q-test <1×10−6). Genomic control was applied to each study (Table S1) and the final meta-analyses (λGC=1.02 for MAP and λGC=1.00 for PP; and Figure S1).

Stage 2: Replication Studies and Joint Analyses

Novel SNPs were selected for stage 2 replication genotyping by choosing the most significant SNP from loci which achieved a stage 1 P<1.0×10−5 for MAP or PP. We considered physiological plausibility by also selecting SNPs located within candidate genes20 if they achieved P<1.0×10−4 for either MAP or PP or P<1.0×10−3 for both MAP and PP. For assessment of transethnic replication, previously identified MAP and PP SNPs15 that achieved nominal significance (P<0.05) in stage 1 study were selected for evaluation in the in silico replication stage.

In silico or de novo replication genotyping and association analyses were conducted in up to 6 additional samples of 28 783 participants (Table 1, Supplementary Note). Meta-analysis was again used to combine results across the stage 2 studies and conduct joint analysis of stage 1 and stage 2 findings. For novel loci, findings were considered significant if they achieved genome-wide significance (P<5.0×10−8) in the joint analysis. For loci previously identified in European populations, a Bonferroni P<1.35×10−3 and consistency in effect direction were considered evidence of replication.

Results

In the stage 1 GWAS meta-analysis of 26 600 participants, genome-wide significance was achieved at 12q21.33 (rs17249754) at the widely reported ATP2B1 locus for the MAP phenotype (P=3.65×10−12; Figure 1 and Table 2). For PP, novel loci TCL6 at 14q32.13 (rs2145975; P=1.90×10−8) and TTC39C at 18q11.2 (rs11874765; P=3.14×10−8) achieved genome-wide significance in stage 1 study (Figure 1 and Table S2). Six additional novel MAP and PP loci achieved borderline significance (P<1.0×10−6; Figure 1 and Table S2). A full list of stage 1 probability values for the associations between each of the 2.4 million SNPs and the MAP and PP phenotypes are publicly available for download at http://www.agenconsortium.org/public_files.php.

Table 2. Transethnic Replication of MAP and PP Loci Among East Asian Samples of the AGEN Consortium

LocusMarkerChromosomePosition (Build 36.3)Nearest GeneCA/OACAFStagesMAPPPPreviously Reported Phenotype
Nβ*SEP Valueβ*SEP Value
3p21.31rs319690347902488MAP4T/C0.71Stage 126 2630.280.122.06E-020.110.113.42E-01MAP
Stage 255830.200.223.65E-010.060.217.65E-01
Stages 1+231 8450.260.111.36E-020.100.103.28E-01
4q21.21rs13149993481377319FGF5A/G0.41Stage 125 9640.320.114.57E-030.370.115.67E-04MAP
Stage 254950.510.211.35E-020.060.207.56E-01
Stages 1+231 4590.370.102.39E-04§0.300.091.51E-03
5p13.3rs1173771532850785NPR3A/G0.37Stage 126 399−0.280.111.30E-02−0.250.111.84E-02MAP, PP
Stage 25477−0.080.217.05E-010.110.195.62E-01
Stages 1+231 876−0.240.101.84E-02−0.170.097.39E-02
10q24.32rs382475510104585839CYP17A1C/G0.32Stage 126 130−0.500.122.42E-05−0.280.111.46E-02MAP, PP
Stage 25571−0.510.211.65E-02−0.250.202.12E-01
Stages 1+231 700−0.500.101.21E-06§−0.270.106.12E-03
10q24.33rs1119159310104929205NT5C2T/C0.74Stage 126 0440.600.132.76E-060.380.121.50E-03MAP, PP
Stage 255770.370.231.15E-010.210.223.26E-01
Stages 1+231 6210.540.111.13E-06§0.340.111.14E-03§
12q21.33rs26814921288537220ATP2B1T/C0.67Stage 116 9150.550.151.65E-040.190.151.94E-01MAP, PP
Stage 255770.730.214.47E-040.510.198.81E-03
Stages 1+222 4920.610.123.39E-07§0.310.129.02E-03
12q21.33rs172497541288584717ATP2B1A/G0.35Stage 125 401−0.820.123.65E-12−0.400.112.76E-04MAP, PP
Stage 25504−0.750.214.55E-04−0.490.201.37E-02
Stages 1+230 905−0.800.107.48E-15§−0.420.101.21E-05§

CA indicates coded allele; CAF, CA frequency; MAP, mean arterial pressure; N, effective sample size; OA, other allele; Position, physical position (in base pairs); PP, pulse pressure.

*β is the effect size in millimeters of mercury per coded allele based on an additive genetic model.

Corresponding marker lays within reported gene.

The variant (or its proxy [r 2>0.8]) was previously implicated for systolic blood pressure or diastolic blood pressure in the genome-wide association study meta-analysis of East Asians conducted by Kato et al.6

§Significant after Bonferroni correction for 37 statistical tests.

Although there is evidence of significance for PP, this variant was only identified for MAP in the study by Wain et al.15 Therefore, this does not represent evidence of transethnic replication of rs1004467, a proxy for rs3824755 in East Asian samples (r2=0.95), achieved genome-wide significance for MAP in the study by Wain et al.15

rs11191548, a proxy for rs1191593 in East Asian samples (r2=1.00), achieved genome-wide significance for PP in the study by Wain et al.15

Figure 1.

Figure 1. Genome-wide association study (GWAS) meta-analysis results for mean arterial pressure (A) and pulse pressure (B). Loci highlighted in red indicate the 2-Mb regions of single-nucleotide polymorphisms (SNPs) that achieved genome-wide significance in stage 1 and joint analyses of stage 1 and stage 2 studies. Loci highlighted in black indicate the 2-Mb regions of SNPs that achieved borderline significance (P<1E-6) in the stage 1 GWAS meta-analysis. Loci highlighted in blue indicate the 2-Mb regions of SNPs that achieved genome-wide significance in the GWAS meta-analysis of Europeans (unless achieving P<1E-6 in the current study).15 Loci that achieved genome-wide significance in Europeans15 or East Asians are labeled (blue if originally identified in Europeans; black if originally identified in the current study).

A total of 35 independent, novel trait-associated SNPs were selected for stage 2 replication study. None achieved genome-wide significance in joint analysis of stage 1 and stage 2 findings (Table S2). Among 48 SNPs that previously achieved genome-wide significance for MAP or PP traits in European populations,15 11 independent loci achieved nominal significance in the stage 1 study and were followed up in stage 2 study (Table S3).

Table 2 provides top transethnic replication results. For the MAP phenotype, rs17249754 at ATP2B1 achieved genome-wide significance in the joint analysis of stage 1 and stage 2 studies (P=7.48×10−15). Four additional SNPs showed robust evidence of replication for MAP (consistency of effect direction and significance after adjustment for multiple testing), including rs13149993 at FGF5 (P=2.39×10−4), rs3824755 at CYP17A1 (P=1.21×10−6), rs11191593 at NT5C2 (1.13×10−6), and rs2681492 at ATP2B1 (P=3.39×10−7). Furthermore, 2 SNPs showed suggestive replication (consistency of effect direction and nominal significance [P<0.05]), including rs319690 at MAP4 (P=0.01) and rs1173771 at NPR3 (P=0.02). For the PP phenotype, robust evidence of replication was identified for 2 SNPs including rs11191593 at NT5C2 (P=1.14×10−3) and rs17249754 at ATP2B1 (P=1.21×10−5). Suggestive evidence of replication was identified for 2 additional SNPs including rs3824755 at CYP17A1 (P=6.12×10−3) and rs2681492 at ATP2B1 (P=9.02×10−3). Effect sizes of replicated MAP and PP loci were very similar between the previous GWAS meta-analysis of Europeans15 and the current GWAS meta-analysis of East Asians (Figure 2).

Figure 2.

Figure 2. Effect sizes and coded allele frequencies (CAFs) for single-nucleotide polymorphisms (SNPs) that showed evidence of transethnic replication for mean arterial pressure (A) and pulse pressure (B) in East Asian participants of the current GWAS meta-analysis. Effect sizes in the current study of East Asians are shown in black whereas those of the previous GWAS meta-analysis of Europeans15 are shown in red.

Discussion

The current meta-analysis of 26 600 East Asian participants provided robust transethnic replication evidence for 5 independent SNPs at MAP and PP loci previously identified in populations of European ancestry,15 including rs13149993 at FGF5, rs3824755 at CYP17A1, rs11191593 at NT5C2, rs2681492 at ATP2B1, and rs17249754 at ATP2B1. In addition, 2 SNPs, rs319690 at MAP4 and rs1173771 at NPR3, showed suggestive evidence of transethnic replication. Further examination of these 7 variants demonstrated remarkable consistency in per allele effect sizes across populations of East Asian and European ancestry.

Seven SNPs from MAP and PP loci identified in samples of European ancestry showed evidence of transethnic replication in the current study of East Asians. Marker rs17249754 at the ATP2B1 locus (12q21.33) achieved genome-wide significance for MAP and was robustly associated with PP. Furthermore, rs2681492, a moderately correlated intronic ATP2B1 SNP (r2=0.78), also showed evidence of transethnic replication for the MAP and PP phenotypes. ATP2B1 is a widely reported BP-related gene, with marker rs17249754 also identified for the SBP and DBP phenotypes in East Asians.47,15ATP2B1 is thought to exert its influence on BP regulation through alteration of calcium handling and vasoconstriction in vascular smooth muscle cells.21 At 3p21.31, the current study provided the first evidence of association for marker rs319690 with a BP-related phenotype among individuals with East Asian ancestry. Marker rs319690 represents an intronic variant of the MAP4 gene, implicated in heart failure through its interference with β-adrenergic receptor recycling.22 At the FGF5 locus (4q21.21), marker rs13149993 was associated with both MAP and PP phenotypes in the current study. The FGF5 rs13149993 variant (or a proxy [r2>0.8]) has been reported previously for its associations with not only MAP but also other BP-related phenotypes.5,7,15 Furthermore, a variant modestly correlated with rs13149993 at FGF5, rs16998073 (r2=0.49), was previously related to SBP and DBP in East Asians.6,23FGF5, a fibroblast growth factor gene, is expressed in cardiac myocytes and has been shown to promote angiogenesis in the heart.24 Near NPR3 (at 5p13.3), rs1173771 was associated with MAP in the current study. Previously reported for its association with MAP in whites and other BP phenotypes in whites and East Asians,6,7,15NPR3 encodes the natriuretic peptide receptor C, a peptide known to regulate BP and fluid homeostasis by modifying glomerular filtration rate and sodium urinary excretion.25 Finally, moderately correlated SNPs rs3824755 and rs11191593 (r2=0.67) at 10q24.32 and 10q24.33, respectively, were associated with MAP and PP in the current study. Marker rs3824755 is an intronic variant of CYP17A1, the gene responsible for the monogenic BP disorder congenital adrenal hyperplasia,26 whereas rs11191593 is an intronic variant of NT5C2, a gene involved in DNA synthesis with no known functional role in BP regulation.27 Marker rs3824755 (or a proxy) was previously reported to associate with not only MAP and PP15 but also SBP in the article by Levy et al,4 whereas rs11191593 (or a proxy) has been reported previously for numerous BP phenotypes, including SBP and DBP in East Asians.57,15

The current GWAS meta-analysis represents the largest genetic association study of MAP and PP conducted in participants of East Asian ancestry to date. Additional study strengths include the adherence of all studies to a standard analytic protocol and stringent genotyping and imputation quality control procedures at the study and meta-analysis levels. Despite these strengths, the current study failed to identify any novel loci related to MAP and PP traits. Although currently this was the largest study conducted in East Asians, the stage 1 sample was only one-third the size of that of the prior GWAS meta-analysis of MAP and PP conducted in populations of European ancestry.15 Thus, we still may have lacked the statistical power needed to identify novel variants for MAP and PP. Furthermore, we did not replicate 24 of the 31 loci previously identified in Europeans. Lack of replication could be related to differences in linkage disequilibrium (LD) patterns between Europeans and East Asians. To address this concern, we examined interpopulation LD variation at these loci.28 Our results showed that LD structure was generally similar between populations at all but 5 regions (see Figure S2). However, examination of variants in LD with the lead SNP in Europeans did not reveal any further significant associations in East Asians, suggesting that differences in LD may not have been a major factor limiting replication in the current study (data not shown). Lack of replication could also be attributable to limited statistical power. To assess this issue, we compared effect sizes and minor allele frequencies of independent SNPs which achieved genome-wide significance in Europeans between the 2 studies (Table S4). Despite differences in the minor allele frequency of many of the variants, very strong correlations in effect sizes between populations were observed (Table S4). Furthermore, power calculations demonstrated that we lacked the statistical power to detect associations for the 24 unreplicated loci (Table S5). These data suggest the existence of additional promising MAP and PP loci in East Asian populations that may be identified by future, larger GWAS meta-analyses.

Perspectives

The current study of 26 600 East Asian participants from 9 GWAS provides the first evidence of transethnic replication of 7 MAP and PP loci previously identified in populations of European ancestry. In addition, we demonstrate remarkable consistency in allelic effect sizes between populations with vast differences in not only genomic ancestry but also environmental and cultural factors. Our findings add to the accumulating evidence that many genomic associations are reproducible in populations with distinct LD structure, suggesting common genomic mechanisms underlying the development of hypertension and cardiovascular disease across populations.

Footnotes

*These authors contributed equally to this work.

†These authors jointly directed this work.

The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.113.01148/-/DC1.

Correspondence to Tanika N. Kelly, Department of Epidemiology, Tulane University, 1440 Canal St, Suite 2000, New Orleans, LA 70112. E-mail

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Novelty and Significance

What Is New?

  • The current genome-wide association study meta-analysis of 26 600 East Asians provides the first evidence of transethnic replication of 7 mean arterial pressure and pulse pressure loci previously identified in populations of European ancestry.

  • Per allele effect sizes of replicated variants were consistent between Europeans and East Asians.

What Is Relevant?

  • The physiological effects of many common polymorphisms may be generalizable across populations.

Summary

The current meta-analysis of 26 600 East Asian participants from 9 genome-wide association study provided evidence of transethnic replication for 7 mean arterial pressure and pulse pressure variants previously identified in populations of European ancestry.15 These variants demonstrated remarkable consistency in per allele effect sizes across populations of East Asian and European ancestry. We add to the accumulating evidence that many genomic associations are reproducible in populations with distinct linkage disequilibrium structure, suggesting common genomic mechanisms underlying the development of hypertension and cardiovascular disease across populations.

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