Genome-wide Association Study Of Body Composition Index And Association Of SOST Gene Polymorphisms With Peak BMD

Chapterl.Association of SOST gene polymorphisms with peak bone mineral density in Chinese nuclear families with male offspringObjective:The purpose of this study was to investigate whether polymorphisms or haplotypes in sclerosteosis(SOST)gene are associated with variation of peak bone mineral density in young men of Shanghai.Methods:10 tagged single nucleotide polymorphisms in SOST gene(rs 1234612,rs1513670,rsl634330,rsl708635,rs2023794,rs7220711,rs74252774,rs851057,rs851058 and rs865429)were genotyped in 1181 individuals of Shanghai from 389 nuclear families with male offspring comprising 778 parents and 403 sons in this study.The nuclear families were composed of at least one male offspring between 20 and 40 years old:the average family size is 3.04.The height and weight were measured.The peak bone mineral density(BMD)of the lumbar spine(LI-4),femoral neck and total hip was measured by dual-energy X-ray absorptiometry(DXA).The association between a single nucleotide polymorphism(SNP)or a haplotype and peak BMD variation was measured using quantitative transmission disequilibrium test(QTDT).P<0.05 was considered significant.Results:No significant within-family associations were found between genotypes or haplotypes of the SOST gene and peak BMD at LI-4,femoral neck and total hip using QTDT.The 1000 permutations were in agreement with these within-family association results.Conclusion:Our present results suggest the natural variation of 10 tag SNPs in SOST gene is not a major contributor to the observed variability in peak BMD in young men of Shanghai.Chapter 2.Association of SOST gene polymorphisms with obesity phenotypes in Chinese nuclear families with male offspringObjective:This study aimed to investigate whether polymorphisms or haplotypes in SOST gene are associated with variation of obesity phenotypes in young men of Shanghai.Methods:We recruited a total of 1,016 individuals of Shanghai from 335 Chinese nuclear families with male offspring,including 670 parents and 346 sons.The nuclear families were composed of at least one male offspring between 20 and 40 years old;the average family size is 3.03.The data of genotypes of 10 tagged SNPs in SOST gene,height,weight and peak BMD of different sites of all the above people were come from Chapter 1.Obesity phenotypes of all the sons were measured by DXA.The associations of the SNPs and haplotypes with obesity phenotypes were analyzed using the QTDT and covariance(ANCOVA)statistical methods.The associations of body composition with various measures of peak BMD were analyzed by Pearson correlation analysis.The relative contribution of lean and fat mass to the peak BMD at various sites was evaluated by multiple linear regression.P<0.05 was considered significant.Results:The 1000 permutations of QTDT were found that the associations between rsl513670 and arms FM and trunk FM(P=0.0410 and P=0.0230,respectily),and rs 1634330 and trunk LM(P=0.0410),however,the haplotypes of SOST gene were not found to be significantly associated with the obesity phenotypes.The trunk FM in TT genotype was lower compared with CT genotype in rs1513670 using ANCOVA(P=0.0470).The FM and LM were positively correlation with peak BMD in all sites using Pearson correlation analysis.The multiple regression analysis showed that LM has a greater effect than FM on peak BMD;they explained 14.8-20.1%and 4.9-5.7%of the peak BMD variance in young men,respectively.Conclusions:The rsls13670 in SOST gene is the quantitative trait locus of variation of arms and trunk FM;and the rs1634330 in SOST gene is the quantitative trait locus of variation of trunk LM in young men of Shanghai.LM is a significantly stronger predictor of peak BMD in young men of Shanghai.Chapter 3.Genome-wide association study of body composition indexObjective:This study aimed to investigate whether the SNPs or the gene pathways associated with FM in different sites of Chinese Han population by genome-wide association analysis(GWAS).Methods:The healthy males aged 20-40(n=346)and premenopausal women aged 20-40(n=239)and postmenopausal women aged 50-80(n=341)were recruited in this study.The 570,378 SNPs of every individual were genotyped using Illumina Human Asian Screening Array-24+v1.0(ASA).The FM of arms,legs,trunk and total body were measured by DXA.The association between FM of all the sites and SNPs were tested by Spearman correlation analysis,P<10-6 was considered significant.The association between FM of all the sites and whole genome pathway were analyzed by man2auc software,P<10-5 was considered significant.Results:The rsl41206415 in RASAL1 gene and rsl44493374 in PALLD gene were associated with trunk FM(P=4.84×10-7 and P=7.49×10-7,respectily);the rs74389755 in DLEU1 and DLEU2 gene was associated with arms and total FM(P=5.50×10-7 and p=1.01×10-6,respectily);and the rs4807023 in PTPRS gene was associated with legs FM(p=1.01×10-6)using Spearman correlation analysis.The association between FM with whole genome pathway showed that trunk FM and total FM were associated with the gene pathway of olfactory receptor activity(P=1.8×10-13 and P=9.56×10-14,respectily),while arms FM and legs FM were associated with the gene pathway of sensory perception of chemical stimulation(p=3.76×10-7 and P=5.85×10-14,respectily).Conclusions:The rsl41206415 in RASAL1 gene and rsl44493374 in PALLD gene are the quantitative trait locus of variation of trunk FM;and rs74389755 in DLEU1 and DLEU2 gene is the quantitative trait locus of variation of arms and total FM;and the rs4807023 in PTPRS gene is the quantitative trait locus of variation of legs FM.The trunk FM and total FM were associated with the gene pathway of olfactory receptor activity,and arms FM and legs FM were associated with the gene pathway of sensory perception of chemical stimulation.