| Objective:Hypertension and obesity,being caused by both genetic and environmental factors,are public health challenges worldwide.Blood pressure and body mass index?BMI?are important indicator of hypertension and obesity.The heritability and related susceptible loci of BMI,systolic pressure?SBP?,and diastolic pressure?DBP?,have been studied in many researches.However,few studies focused on bivariate or multivariate association between blood pressure and BMI.Therefore,bivariate structural equation models and genome-wide association studies?GWAS?of three pairs of phenotypes,BMI-SBP,BMI-DBP and SBP-DBP,were performed to explore the single nucleotide polymorphisms?SNPs?,genes and pathways in this study.Methods:The participants were recruited from Qingdao twin registry system with signing consent forms.All twin pairs were used to evaluate the genetic correlations,and 137 dizygotic pairs were used in GWAS study.After collecting fasting blood and examination data,zygosity was identified by sex,blood type,and further DNA markers.We used Mx software to compose bivariate Cholesky decomposition model and then access the genetic and environmental effects on phenotypic correlation.DNA samples of 137 dizygotic twin pairs were genotyped using the Illumina's Infnium Omni2.5Exome-8v1.2 BeadChip-platform?Illumina,San Diego,California,USA?.IMPUTE2 software was used to impute un-typed SNPs.Genome-wide efficient mixed model analysis?GEMMA?was performed in SNPs-based analysis.In addition,gene-based analysis and enrichment analysis were performed by VEGAS2?Versatile Gene-based Association Study-2?and PASCAL,respectively.Results:A total of 380 twin pairs,including 137 dizygotic pairs were included.The mean age of participants was 51.5±7.6 years;the mean BMI was 24.3±3.3 kg/m2,and mean SBP and DBP were 130.8±20.1mmHg and 83.1±10.9mm Hg,respectively.?1?Bivariate genetic correlations of BMI-SBP,BMI-DBP,and SBP-DBP were 0.2108,0.2345,and 0.6942,respectively,after adjusting age and sex.?2?In the SNP-based analysis,although no statistically significant SNPs were found(P<5×10-8),we nominated 27 SNPs exceeding suggestive significance(P<1×10-5)in analysis of both BMI-SBP and BMI-DBP,and 25 SNPs in analysis of SBP-DBP.The related SNPs with BMI-SBP,BMI-DBP,and SBP-DBP were 1:201008796,locating in KIF21B?P=2.94×10-7?;rs2025924 near LINC00343(P=4.28×10-7);and rs113511958 locating in SPINK1(P=5.14×10-7).After performing imputing analysis,there were 9 SNPs exceeding statistically significant threshold,of which the SNPs with the smallest P value with BMI-SBP,BMI-DBP and SBP-DBP were:7:19534588 near TMEM196(P=2.06×10-8);rs7987025 near LINC00343(P=7.66×10-8),and rs61118809 locating in TENM4(P=6.84×10-10),respectively.More SNPs were located in the same area and related to more than one pairs of phenotypes in the imputing analysis.?3?In the gene-based analysis,although no statistically significant gene was found,we found that 1043,1103,1100 genes were related to BMI-SBP,BMI-DBP and SBP-DBP,respectively?P<0.05?.PHOSPHO1 was related to both BMI-SBP and BMI-DBP with smallest P value.LINC00346 was related to SBP-DBP with smallest P value.Nine genes such as PHOSPHO1,GNGT2,KEAP1 and S1PR5 were found in the result of both BMI-SBP and BMI-DBP.LOC102724596,NAP1L1 and PSMB3 were found in the result of both BMI-SBP and SBP-DBP.Six genes such as LINC00346,FMO9P,TFF2 were found in the result of both BMI-DBP and SBP-DBP.Also,there were some consistent genes both in gene-based analysis and SNP-based analysis.?4?In the pathway analysis,628,599,and 766 pathways were found significantly associated with BMI-SBP,BMI-DBP and SBP-DBP,respectively?P<0.05?.The pathways associated with BMI-SBP,BMI-DBP and SBP-DBP were prion diseases,IL5 pathway,and cyclin E associated events during G1/S transition,respectively.The other relative pathways mainly involved TGF beta signaling pathway,ADP signaling through P2RY1,neuroactive ligand receptor interaction pathways etc.Conclusion:BMI and blood pressure might share some same genetic mechanism in Qingdao twins.We found the lower bivariate genetic correlations of BMI-SBP and BMI-DBP,and relatively higher bivariate genetic correlations of SBP-DBP.We found some SNPs,genes and pathways were associated with blood pressure and BMI,which enriched the result of GWAS in this field,and provided some evidences to future pathogenesis of hypertension and obesity in East Asian population. |
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