Ichikawa Shoji, Koller Daniel L, Curry Leah R, Lai Dongbing, Xuei Xiaoling, Pugh Elizabeth W, Tsai Ya-Yu, Doheny Kimberly F, Edenberg Howard J, Hui Siu L, Foroud Tatiana, Peacock Munro, Econs Michael J
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202-5121, USA.
J Bone Miner Res. 2008 Oct;23(10):1680-8. doi: 10.1359/jbmr.080509.
Osteoporosis is a complex disease with both genetic and environmental risk factors. A major determinant of osteoporotic fractures is peak BMD obtained during young adulthood. We previously reported linkage of chromosome 1q (LOD = 4.3) with variation in spinal areal BMD in healthy premenopausal white women. In this study, we used a two-stage genotyping approach to identify genes in the linked region that contributed to the variation of femoral neck and lumbar spine areal BMD. In the first stage, 654 SNPs across the linked region were genotyped in a sample of 1309 premenopausal white women. The most significant evidence of association for lumbar spine (p = 1.3 x 10(-6)) was found with rs1127091 in the GATAD2B gene. In the second stage, 52 SNPs around this candidate gene were genotyped in an expanded sample of 1692 white women. Significant evidence of association with spinal BMD (p < 10(-5)), and to a lesser extent with femoral neck BMD, was observed with eight SNPs within a single 230-kb linkage disequilibrium (LD) block. The most significant SNP (p = 3.4 x 10(-7)) accounted for >2.5% of the variation in spinal BMD in these women. The 230-kb LD block contains 11 genes, but because of the extensive LD, the specific gene(s) contributing to the variation in BMD could not be determined. In conclusion, the significant association between spinal BMD and SNPs in the 230-kb LD block in chromosome 1q indicates that genetic factor(s) in this block plays an important role in peak spinal BMD in healthy premenopausal white women.
骨质疏松症是一种具有遗传和环境风险因素的复杂疾病。骨质疏松性骨折的一个主要决定因素是年轻时获得的峰值骨密度。我们之前报道了1号染色体（LOD = 4.3）与健康绝经前白人女性脊柱面积骨密度变化的连锁关系。在本研究中，我们采用两阶段基因分型方法来鉴定连锁区域中导致股骨颈和腰椎面积骨密度变化的基因。在第一阶段，对1309名绝经前白人女性样本中连锁区域的654个单核苷酸多态性（SNP）进行了基因分型。在GATAD2B基因中的rs1127091处发现了与腰椎最显著的关联证据（p = 1.3 x 10(-6)）。在第二阶段，对1692名白人女性的扩大样本中该候选基因周围的52个SNP进行了基因分型。在一个单一的230 kb连锁不平衡（LD）区域内的8个SNP中，观察到与脊柱骨密度有显著关联证据（p < 10(-5)），与股骨颈骨密度的关联程度较小。最显著的SNP（p = 3.4 x 10(-7)）占这些女性脊柱骨密度变化的2.5%以上。这个230 kb的LD区域包含11个基因，但由于广泛的LD，无法确定导致骨密度变化的具体基因。总之，1号染色体上230 kb LD区域中脊柱骨密度与SNP之间的显著关联表明，该区域的遗传因素在健康绝经前白人女性的峰值脊柱骨密度中起重要作用。
