Heritability And Genome-wide Association Study Of Blood Pressure In Adult Twins

Background:Blood pressure（BP）is an important indicator of human heart function and peripheral vascular resistance.It is also a predictor of many chronic diseases,such as cardiovascular diseases and diabetes.Systolic blood pressure（SBP）,diastolic blood pressure（DBP）,pulse pressure（PP）,and mean arterial pressure（MAP）are all commonly used indicators for detecting BP in the clinic.BP can be affected by genetic and environmental factors.However,the number of genomic-wide association study（GWAS）related to blood pressure in China is relatively small.Therefore,this study mainly explores the influence of genetic factors on SBP,DBP,PP,and MAP,as well as using GWAS to further find genetic susceptibility sites,genes and biological pathways related to BP.Methods:Eligible twins were selected from the Qingdao Twins Registration System based on the inclusion exclusion criteria,and all the study subjects signed informed consent.Data on the BP of subjects were obtained from the results of the physical examination.The zygosity of twin was gradually identified by the sex,ABO blood type,and microsatellite DNA gene scanning and typing technology.Mx software package was used to construct the structural equation model,the model was selected after adjusting age,gender,and body mass index（BMI）,and the heritability（h²）of SBP,DBP,PP,and MAP were calculated based on the results of the best model.InfiniumOmni2.5Exome-8v1.2 chip platform（Illumina）was used to genotype whole genome SNPs.Impute2 software was used to impute untyped SNPs.During genotyping and imputation,strict quality control standards were used to screen SNPs.At GWAS analysis,GEMMA（Genome-wide Efficient Mixed Model Association）was used to perform SNPs-based analysis to find some SNPs related to SBP,DBP,PP,and MAP;VEGAS2（Versatile Gene-based Association Study-2）was used to perform gene-based analysis;PASCAL（Pathway enrichment analysis）was used to conduct for pathway-based analysis.In the SNPs-based analysis,Q-Q plots were used to investigate whether the population was stratified,and Manhattan plots were used to represent significant SNPs.Results:A total of 380 pairs of twins were included in this study,including 243 pairs of monozygotic（MZ）twins and 137 pairs of dizygotic（DZ）twins.380 pairs of twins were used to perform heritability analysis and 137 pairs of DZ twins were used to conduct GWAS analysis.The average age of subjects was 51.52±7.62 years.The average±standard deviation of SBP,DBP,PP,and MAP were 130.76±20.09 mmHg,83.06±10.88 mmHg,47.70±14.66 mmHg,and 98.96±12.87 mmHg,respectively.The correlations of MZ twin for SBP,DBP,PP,and MAP were 0.53,0.50,0.47,and 0.53,and the correlations of DZ twin for SBP,DBP,PP,and MAP were 0.30,0.28,0.29,and 0.27,respectively.The correlations of MZ twin for SBP,DBP,PP,and MAP were less than twice that of DZ twin,so,the ACE model was selected.Then the likelihood ratio chi-square test,the simplest principle and Akaike information criterion were used to determine the most suitable nested models of SBP,DBP,PP,and MAP.The most suitable nested models of SBP,DBP,PP,and MAP were AE models.The heritability of SBP,DBP,PP,and MAP was 53.70%,50.10%,48.10%and 53.30%,respectively.A total of 1,364,336 eligible SNPs was included in GWAS.In SNPs-based analysis,Q-Q plots for SBP,DBP,PP,and MAP all indicated that there was no population stratification.The Manhattan plots showed that although none of the SNPs exceeded the significance level(P<5×10^-8),three,four,fourteen,and nine SNPs exceeded the suggested significance level(P<1×10^-5),respectively.The most significant SNPs of SBP,DBP,PP,and MAP were rs34710727 on chromosome 1,rs78992800 on chromosome 13,rs72815554on chromosome 5,and rs1560125 on chromosome 5.No SNP was found to reach the genome-wide significance level in post-imputation Manhattan plots of SBP,DBP,PP and MAP.While,46,37,91 and 61 SNPs were found to exceed the threshold of suggestive significance level for SBP,DBP,PP and MAP,respectively.No gene was found to achieve genome-wide significance level（P<0.05）in gene-based analysis,but 1083,1131,1104 and1122 genes were nominally associated with SBP,DBP,PP and MAP,respectively.In further analysis,53 common genes were found among SBP,DBP,PP and MAP,including THRB,PSMB3,OR8D1 and so on.In the pathway-based analysis,672,706,701 and 596 pathways were found to be associated with SBP,DBP,PP and MAP,respectively（P<0.05）,including EGFR-SMRTE-PATHWAY,DILATED-CARDIOMYOPATHY,GAB1-SIGNALOSOME,and so on.Conclusion:Our study indicated the SBP,DBP,PP,and MAP of the twins in Qingdao were moderately inherited.And some SNPs related to SBP,DBP,PP and MAP were found in our study,such as rs34710727,rs78992800,rs72815554 and rs1560125;some genes related to SBP,DBP,PP and MAP were found,such as THRB,FMO9P,ZNF576 and LINC00346;some related pathways were found,such as EGFR-SMRTE-PATHWAY,DILATED-CARDIOMYOPATHY and GAB1-SIGNALOSOME,which provided relevant clues for the future molecular biology research of BP.The discovered biomarkers can be used as a reference for subsequent repetition and verification or as a target for clinical diagnosis and treatment,etc.