Association Study Of Bone Mineral Density And Exon Sequence Of Human STAT1and WNT16Genes In Chinese Population

Aim:Previous lots of researches showed that the STAT1gene and WNT16gene played a vital role in variation of human BMD. SNP rs11699463residing in STAT1is associated with BMD at spine. Previous studies indicated that the importance of Wnt signaling pathway for bone metabolism and the common functional variation rs2707466reside in WNT16gene was strongly involved in human bone mineral density (BMD). In the present study, rare variation association analyses were performed to validate the effect of rare functional variation in STAT1and WNT16on human BMD.Methods:There were50high and51low hip BMD subjects to be selected from about2000Chinese random subjects in Changsha and Xi’an in China. All BMD data were measured by Hologic QDR-4500W dual-energy X-ray absorptiometry (DXA). The hip BMD was distributed as a dichotomous trait, while spine and wrist BMD were distributed as quantitative traits and adjusted with covariates age, age2, height and weight. DNA was extracted from peripheral blood for Exome captured by NimbleGen2.1M Human Exome Array and re-sequenced by Illumina Solexa. Variable threshold test (VT) analyses were performed for rare variation association detection with BMD.Results:In this study,45variants were detected in STAT1exon region in Chinese Han population through exon re-sequence. Of these45variants,6were synonymous.115variants were detected in Caucasian subjects, including1synonymous. We didn’t observe an significant relationship between variation of BMD and STAT1gene through pooled association test. In WNT16exons,6variants were detected, including4missense and2synonymous mutations. All the missense variants were associated with wrist BMD (P=0.0009), hip BMD (P=0.0139), and spine BMD (P=0.0079). In only rare variation analyses with Minor Allele Frequency (MAF) less than0.05, WNT16gene was still associated with wrist BMD (P=0.0009). In a replication study in44Caucasians with high and low BMD groups, there was no rare missense variation in WNT16gene, but two common missense SNPs rs2707466and rs2908004were detected and rs2707466was significantly associated with hip BMD (P=0.017). Both rare missense variants (Leu15Met and Lys61Asn) were predicted as damaging roles in WNT16protein. The frequencies of rs2707466and rs2908004were much different in Asian, Caucasian and African populations.Conclusion:We can’t validate the effect of rare variants residing STAT1gene on BMD changes. But the common missense variant rs2707466and the rare missense variants in WNT16were all important for the variation of human BMD. This is the first research to identify the new rare missense mutations in WNT16and to reveal the effect on human bone metabolism in different ethnic populations.