Objective Osteoporosis has become a severe public health problem . Variation in bone geometry has played an important role in osteoporosis development . But its genetic mechanism re-mains to be identified . Methods In the present study , aiming to identify genetic loci associated with femoral neck shaft cross-sectional area ( CSA ) , we conducted a genome-wide association study in the Framingham Heart Study involvoing 5822 pedigree participants . All involved participants were measured by a dual energy X-ray bone-densitometer , and were genotyped by the Affymetrix high-throughput genotyping array . The 1000 genome project sequence variants were used to impute un-typed genotypes . Results Our analyses identified a novel locus 10 q 13 ( rs 1963966 , P =3 . 17 × 10 -8 ) for CSA at the genome-wide significance level (α =5 . 0 × 10 -8 ) . Bioinformatics and functional analyses demonstrated that the leading SNP and its neighboring SNPs have potential promoter and enhancer activities in osteoblasts , fur-ther strengthening the evidence of its regulatory role to bone development . Conclusion Our findings not only provide useful insights that enhance our understanding of bone development , osteoporosis and fracture pathogenesis , but also establish a solid basis for subsequent functional study of the relevant genes .%目的 鉴定髋关节轴横截面积这一骨几何形态主要指标的遗传变异.方法 研究样本来源于美国弗雷明汉心脏病研究(Framingham heart study,FHS),共纳入5822位家系样本的参与者.所有参与者使用双能X射线仪测定骨几何结构,同时使用Affymetrix高通量芯片进行全基因组基因分型.使用千人基因组参考数据对基因型数据补缺后进行关联分析.结果 分析结果在全基因组水平(α=5.0×10-8)鉴定了一个位于10q13区域的显著关联单核苷酸多态位点(single nucleotide polymorphism,SNP)rs 1963966(P=3.17×10-8,相邻基因FRMD 4 A).生物信息学研究发现这个位点及其相邻位点在成骨细胞中具有调节启动子和增强子活性的功能,进一步证实了这个位点对髋关节轴横截面积的调控作用.结论 本研究不仅可以为阐明骨几何形态的形成和代谢提供科学依据,并能为后续的骨质疏松症相关基因功能研究奠定基础.
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