Heritability and genome-wide association study of blood pressure in Chinese adult twins.
Ontology highlight
ABSTRACT: Background
Blood pressure (BP) is an independent and important factor for chronic diseases such as cardiovascular diseases and diabetes.Methods
We firstly conducted twin modeling analyses to explore the heritability of BP, including systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP) and mean arterial pressure (MAP), and then performed genome-wide association studies to explore the associated genomic loci, genes, and pathways.Results
A total of 380 Chinese twin pairs were included. The AE model containing additive genetic parameter (A) and unique/non-shared environmental parameter (E) was the best fit model, with A accounting for 53.7%, 50.1%, 48.1%, and 53.3% for SBP, DBP, PP and MAP, respectively. No SNP was found to reach the genome-wide significance level (p < 5 × 10-8 ), however, three, four, 14 and nine SNPs were found to exceed suggestive significance level (p < 1 × 10-5 ) for SBP, DBP, PP, and MAP, respectively. And after imputation, 46, 37, 91 and 61 SNPs were found to exceed the suggestive significance level for SBP, DBP, PP, and MAP, respectively. In gene-based analysis, 53 common genes were found among SBP, DBP, PP, and MAP. In pathway enrichment analysis, 672, 706, 701, and 596 biological pathways were associated with SBP, DBP, PP, and MAP, respectively (p < 0.05).Conclusion
Our study suggests that BP is moderately heritable in the Chinese population and could be mediated by a series of genomic loci, genes, and pathways. Future larger-scale studies are needed to confirm our findings.
SUBMITTER: Chen J
PROVIDER: S-EPMC8606211 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Dyslipidemia represents a strong and independent risk factor for cardiovascular disease. Plasma cholesterol, such as total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C), is the common indicator of diagnosing dyslipidemia. Here based on 382 Chinese twin pairs, we explored the magnitude of genetic impact on TC, HDL-C, LDL-C variation and further searched for genetic susceptibility loci for them using genome-wide association study (GWAS). The ACE model was the best fit model with additive genetic parameter (A) accounting for 26.6%, common or shared environmental parameter (C) accounting for 47.8%, unique/non-shared environmental parameter (E) accounting for 25.6% for the variance in HDL-C. The AE model was the best fit model for TC (A: 61.4%; E: 38.6%) and LDL-C (A: 65.5%; E: 34.5%). While no SNPs reached the genome-wide significance level (P < 5 × 10-8), 8, 14, 9 SNPs exceeded the suggestive significance level (P < 1 × 10-5) for TC, HDL-C, LDL-C, respectively. The promising genetic regions for TC, HDL-C, LDL-C were on chromosome 11 around rs7107698, chromosome 5 around rs12518218, chromosome 2 around rs10490120, respectively. Gene-based analysis found 1038, 1033 and 1090 genes nominally associated with TC, HDL-C, LDL-C (P < 0.05), especially FAF1, KLKB1 for TC, KLKB1 for HDL-C, and NTRK1, FAF1, SNTB2 for LDL-C, respectively. The number of common related genes among TC, HDL-C and LDL-C was 71, including FAF1, KLKB1, etc. Pathway enrichment analysis discovered known related pathways-zinc transporters, metal ion SLC transporters for TC, cell adhesion molecules CAMs, IL-6 signaling for HDL, FC epsilon RI signaling pathway, NFAT pathway for LDL, respectively. In conclusion, the TC and LDL-C level is moderately heritable and the HDL-C level is lowly heritable in Chinese population. The genomic loci, functional genes and pathways are identified to account for the heritability of plasma cholesterol level. Our findings provide important insights into plasma cholesterol molecular physiology and expect future research to replicate and validate our results.
| S-EPMC6249314 | biostudies-literature
Project description:BackgroundCurrently, diabetes has become one of the leading causes of death worldwide. Fasting plasma glucose (FPG) levels that are higher than optimal, even if below the diagnostic threshold of diabetes, can also lead to increased morbidity and mortality. Here we intend to study the magnitude of the genetic influence on FPG variation by conducting structural equation modelling analysis and to further identify specific genetic variants potentially related to FPG levels by performing a genome-wide association study (GWAS) in Chinese twins.ResultsThe final sample included 382 twin pairs: 139 dizygotic (DZ) pairs and 243 monozygotic (MZ) pairs. The DZ twin correlation for the FPG level (rDZ = 0.20, 95% CI: 0.04-0.36) was much lower than half that of the MZ twin correlation (rMZ = 0.68, 95% CI: 0.62-0.74). For the variation in FPG level, the AE model was the better fitting model, with additive genetic parameters (A) accounting for 67.66% (95% CI: 60.50-73.62%) and unique environmental or residual parameters (E) accounting for 32.34% (95% CI: 26.38-39.55%), respectively. In the GWAS, although no genetic variants reached the genome-wide significance level (P < 5 × 10- 8), 28 SNPs exceeded the level of a suggestive association (P < 1 × 10- 5). One promising genetic region (2q33.1) around rs10931893 (P = 1.53 × 10- 7) was found. After imputing untyped SNPs, we found that rs60106404 (P = 2.38 × 10- 8) located at SPATS2L reached the genome-wide significance level, and 216 SNPs exceeded the level of a suggestive association. We found 1007 genes nominally associated with the FPG level (P < 0.05), including SPATS2L, KCNK5, ADCY5, PCSK1, PTPRA, and SLC26A11. Moreover, C1orf74 (P = 0.014) and SLC26A11 (P = 0.021) were differentially expressed between patients with impaired fasting glucose and healthy controls. Some important enriched biological pathways, such as β-alanine metabolism, regulation of insulin secretion, glucagon signaling in metabolic regulation, IL-1 receptor pathway, signaling by platelet derived growth factor, cysteine and methionine metabolism pathway, were identified.ConclusionsThe FPG level is highly heritable in the Chinese population, and genetic variants are significantly involved in regulatory domains, functional genes and biological pathways that mediate FPG levels. This study provides important clues for further elucidating the molecular mechanism of glucose homeostasis and discovering new diagnostic biomarkers and therapeutic targets for diabetes.
| S-EPMC7368793 | biostudies-literature
Project description:Recently, new loci related to body mass index (BMI) or blood pressure (BP) have been identified respectively in genome-wide association studies (GWAS). However, limited studies focused on jointly associated genetic variance between systolic pressure (SBP), diastolic pressure (DBP) and BMI. Therefore, a bivariate twin study was performed to explore the genetic variants associated with BMI-SBP, BMI-DBP and SBP-DBP. A total of 380 twin pairs (137 dizygotic pairs and 243 monozygotic pairs) recruited from Qingdao Twin Registry system were used to access the genetic correlations (0.2108 for BMI-SBP, 0.2345 for BMI-DBP, and 0.6942 for SBP-DBP, respectively) by bivariate Cholesky decomposition model. Bivariate GWAS in 137 dizygotic pairs nominated 27 single identified 27 quantitative trait nucleotides (QTNs) for BMI and SBP, 27 QTNs for BMI and DBP, and 25 QTNs for SBP and DBP with the suggestive P-value threshold of 1×10-5. After imputation, we found eight SNPs, one for both BMI-SBP and SBP-DBP, and eight for SBP-DBP, exceed significant statistic level. Expression quantitative trait loci analysis identified rs4794029 as new significant eQTL in tissues related to BMI and SBP. Also, we found 6 new significant eQTLs (rs4400367, rs10113750, rs11776003, rs3739327, rs55978930, and rs4794029) in tissues were related to SBP and DBP. Gene-based analysis identified nominally associated genes (P < 0.05) with BMI-SBP, BMI-DBP, and SBP-DBP, respectively, such as PHOSPHO1, GNGT2, KEAP1, and S1PR5. In the pathway analysis, we found some pathways associated with BMI-SBP, BMI-DBP and SBP-DBP, such as prion diseases, IL5 pathway, cyclin E associated events during G1/S transition, TGF beta signaling pathway, G βγ signaling through PI3Kγ, prolactin receptor signaling etc. These findings may enrich the results of genetic variants related to BMI and BP traits, and provide some evidences to future study the pathogenesis of hypertension and obesity in the northern Chinese population.
| S-EPMC7861438 | biostudies-literature
Project description:BackgroundHypertension is a crucial risk factor for developing cardiovascular disease and reducing life expectancy. We aimed to detect DNA methylation (DNAm) variants potentially related to systolic blood pressure (SBP) and diastolic blood pressure (DBP) by conducting epigenome-wide association studies in 60 and 59 Chinese monozygotic twin pairs, respectively.MethodsGenome-wide DNA methylation profiling in whole blood of twins was performed using Reduced Representation Bisulfite Sequencing, yielding 551,447 raw CpGs. Association between DNAm of single CpG and blood pressure was tested by applying generalized estimation equation. Differentially methylated regions (DMRs) were identified by comb-P approach. Inference about Causation through Examination of Familial Confounding was utilized to perform the causal inference. Ontology enrichment analysis was performed using Genomic Regions Enrichment of Annotations Tool. Candidate CpGs were quantified using Sequenom MassARRAY platform in a community population. Weighted gene co-expression network analysis (WGCNA) was conducted using gene expression data.ResultsThe median age of twins was 52 years (95% range 40, 66). For SBP, 31 top CpGs (p < 1 × 10-4) and 8 DMRs were identified, with several DMRs within NFATC1, CADM2, IRX1, COL5A1, and LRAT. For DBP, 43 top CpGs (p < 1 × 10-4) and 12 DMRs were identified, with several DMRs within WNT3A, CNOT10, and DAB2IP. Important pathways, such as Notch signaling pathway, p53 pathway by glucose deprivation, and Wnt signaling pathway, were significantly enriched for SBP and DBP. Causal inference analysis suggested that DNAm at top CpGs within NDE1, MYH11, SRRM1P2, and SMPD4 influenced SBP, while SBP influenced DNAm at CpGs within TNK2. DNAm at top CpGs within WNT3A influenced DBP, while DBP influenced DNAm at CpGs within GNA14. Three CpGs mapped to WNT3A and one CpG mapped to COL5A1 were validated in a community population, with a hypermethylated and hypomethylated direction in hypertension cases, respectively. Gene expression analysis by WGCNA further identified some common genes and enrichment terms.ConclusionWe detect many DNAm variants that may be associated with blood pressure in whole blood, particularly the loci within WNT3A and COL5A1. Our findings provide new clues to the epigenetic modification underlying hypertension pathogenesis.
| S-EPMC9985232 | biostudies-literature
Project description:Serum uric acid (SUA), as the end product of purine metabolism, has proven emerging roles in human disorders. Here based on a sample of 379 middle and old-aged Chinese twin pairs, we aimed to explore the magnitude of genetic impact on SUA variation by performing sex-limitation twin modeling analyses and further detect specific genetic variants related to SUA by conducting a genome-wide association study. Monozygotic (MZ) twin correlation for SUA level (rMZ = 0.56) was larger than for dizygotic (DZ) twin correlation (rDZ = 0.39). The common effects sex-limitation model provided the best fit with additive genetic parameter (A) accounting for 46.3%, common or shared environmental parameter (C) accounting for 26.3% and unique/nonshared environmental parameter (E) accounting for 27.5% for females and 29.9, 33.1, and 37.0% for males, respectively. Although no SUA-related genetic variants reached genome-wide significance level, 25 SNPs were suggestive of association (P < 1 × 10-5). Most of the SNPs were located in an intronic region and detected to have regulatory effects on gene transcription. The cell-type specific enhancer of skeletal muscle was detected which has been reported to implicate SUA. Two promising genetic regions on chromosome 17 around rs2253277 and chromosome 14 around rs11621523 were found. Gene-based analysis found 167 genes nominally associated with SUA level (P < 0.05), including PTGR2, ENTPD5, well-known SLC2A9, etc. Enrichment analysis identified one pathway of transmembrane transport of small molecules and 20 GO gene sets involving in ion transport, transmembrane transporter activity, hydrolase activity acting on acid anhydrides, etc. In conclusion, SUA shows moderate heritability in women and low heritability in men in the Chinese population and genetic variations are significantly involved in functional genes and regulatory domains that mediate SUA level. Our findings provide clues to further elucidate molecular physiology of SUA homeostasis and identify new diagnostic biomarkers and therapeutic targets for hyperuricemia and gout.
| S-EPMC5845532 | biostudies-literature
Project description:ObjectivesTo evaluate the associations in twins between within pair differences in birth weight and subsequent blood pressures as adults thereby removing the impact of potential parental confounding variables.DesignHistorical cohort study.SettingSt Thomas's UK adult twin register, June 1992 to September 1995.Participants492 pairs of female twins (mean age 54 years).Main outcome measuresMean within pair differences in adult blood pressure in each of four strata of within pair differences in birth weight (0, 1-500 g, 501-1000 g, >1000 g). Differences in blood pressure were analysed before and after adjustment for potential confounders between adult twins, after exclusion of those twin pairs including at least one twin taking antihypertensive drugs, and by zygosity.ResultsReported mean birth weights of heavier and lighter twins were 2.51 (SD 0.61) v 2.12 (0.59) kg respectively. A graded inverse relation between strata of within pair differences in birth weight and differences in adult blood pressure was apparent, with an adjusted blood pressure range of 8.7/5.1 mm Hg across the four strata (test for trend: systolic, P=0.05; diastolic, P=0.09). After excluding those women taking antihypertensive drugs the significance of the association was similar (systolic, P=0.04; diastolic, P=0.10). When differences in blood pressure were stratified for zygosity similar but non-significant trends were apparent.ConclusionIt would seem that birth weight is inversely associated with adult blood pressure and that this association is independent of parental confounding variables probably including, in view of the findings in monozygotic twins, genetic factors. The observed blood pressure differences are likely to result from retarded intrauterine growth due to placental dysfunction rather than inadequate maternal nutrition.
| S-EPMC28278 | biostudies-literature
Project description:Hypertension is a common disorder and the leading risk factor for cardiovascular disease and premature deaths worldwide. Genome-wide association studies (GWASs) in the European population have identified multiple chromosomal regions associated with blood pressure, and the identified loci altogether explain only a small fraction of the variance for blood pressure. The differences in environmental exposures and genetic background between Chinese and European populations might suggest potential different pathways of blood pressure regulation. To identify novel genetic variants affecting blood pressure variation, we conducted a meta-analysis of GWASs of blood pressure and hypertension in 11 816 subjects followed by replication studies including 69 146 additional individuals. We identified genome-wide significant (P < 5.0 × 10(-8)) associations with blood pressure, which included variants at three new loci (CACNA1D, CYP21A2, and MED13L) and a newly discovered variant near SLC4A7. We also replicated 14 previously reported loci, 8 (CASZ1, MOV10, FGF5, CYP17A1, SOX6, ATP2B1, ALDH2, and JAG1) at genome-wide significance, and 6 (FIGN, ULK4, GUCY1A3, HFE, TBX3-TBX5, and TBX3) at a suggestive level of P = 1.81 × 10(-3) to 5.16 × 10(-8). These findings provide new mechanistic insights into the regulation of blood pressure and potential targets for treatments.
| S-EPMC4303798 | biostudies-literature
Project description:Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 × 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 × 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.
| S-EPMC2998712 | biostudies-literature
Project description:BackgroundChromogranin A (CHGA) triggers catecholamine secretory granule biogenesis, and its catestatin fragment inhibits catecholamine release. We approached catestatin heritability using twin pairs, coupled with genome-wide linkage, in a series of twin and sibling pairs from 2 continents.Methods and resultsHypertensive patients had elevated CHGA coupled with reduction in catestatin, suggesting diminished conversion of precursor to catestatin. Heritability for catestatin in twins was 44% to 60%. Six hundred fifteen nuclear families yielded 870 sib pairs for linkage, with significant logarithm of odds peaks on chromosomes 4p, 4q, and 17q. Because acidification of catecholamine secretory vesicles determines CHGA trafficking and processing to catestatin, we genotyped at positional candidate ATP6N1, bracketed by peak linkage markers on chromosome 17q, encoding a subunit of vesicular H(+)-translocating ATPase. The minor allele diminished CHGA secretion and processing to catestatin. The ATP6N1 variant also influenced blood pressure in 1178 individuals with the most extreme blood pressure values in the population. In chromaffin cells, inhibition of H(+)-ATPase diverted CHGA from regulated to constitutive secretory pathways.ConclusionsWe established heritability of catestatin in twins from 2 continents. Linkage identified 3 regions contributing to catestatin, likely novel determinants of sympathochromaffin exocytosis. At 1 such positional candidate (ATP6N1), variation influenced CHGA secretion and processing to catestatin, confirming the mechanism of a novel trans-QTL for sympathochromaffin activity and blood pressure.
| S-EPMC2654229 | biostudies-literature
Project description:Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ? 71,225 European ancestry, N ? 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
| S-EPMC2891673 | biostudies-literature