Identification of a linkage disequilibrium block in chromosome 1q associated with BMD in premenopausal white women

Abstract

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.

FIG. 1

Stage I association tests using the 609 SNPs in the chromosome 1q region. The chromosome location is shown in the baseline (dbSNP Build 128); −log of p values are shown on the y-axis. The circles indicate rs1127091 in GATAD2B. Blue diamond, lumbar spine BMD; red square, femoral neck BMD.

FIG. 2

LD (D′) structure around the GATAD2B gene. LD was computed between the genotyped SNPs in this region (see Table 3). The pairwise D′ statistic is shown within each box (range, 0–100; 0 indicating no LD; 100 indicating complete LD). The degree of shading represents the extent of LD. Darker shades indicate greater LD, lighter shades indicate less LD. When no number is shown within a box and the box is black, the corresponding D′ is 100 (complete linkage disequilibrium). The two SNPs that define LD block 3 are marked with thick black lines.

FIG. 3

Stage II association tests using the 52 SNPs around GATAD2B. The arrows denote genes located in this region (the orientation in the genome). The chromosome location is shown in the baseline (dbSNP Build 128); −log of p values are shown on the y-axis. The circles indicate rs1127091 in GATAD2B. Blue diamond, lumbar spine BMD; red square, femoral neck BMD.