Polymorphisms in the Low-Density Lipoprotein Receptor–Related Protein 5 (LRP5) Gene Are Associated with Variation in Vertebral Bone Mass, Vertebral Bone Size, and Stature in Whites  Serge L. Ferrari, Samuel Deutsch, Urmila Choudhury, Thierry Chevalley, Jean-Philippe Bonjour, Emmanouil T. Dermitzakis, René Rizzoli, Stylianos E. Antonarakis  The American Journal of Human Genetics  Volume 74, Issue 5, Pages 866-875 (May 2004) DOI: 10.1086/420771 Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 1 Schematic diagram of SNP localization in LRP5. Vertical bars represent the 23 exons of LRP5, and arrows indicate the positions of the eight validated SNPs with a minimum allele frequency of 2%. SNPs encoding missense substitutions are boxed. Leading asterisks (*) indicate SNPs used in the association study. Percentages indicate the frequency of the rare allele. The insert shows LD for all SNP pairs, calculated as R2 values. Gray-shaded coding represents the strength of LD (R2 values), according to the scale shown on the left. Leading asterisks (*) inside the boxes indicate the level of significance for LD; one asterisk (*) denotes P=.01 to .001, and two asterisks (**) denotes P<.001. The American Journal of Human Genetics 2004 74, 866-875DOI: (10.1086/420771) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 2 Differences in adult LS bone measurements and stature, according to LRP5 exon 9 missense SNP and sex. Stature and aBMD, BMC, and bone area at the LS were measured cross-sectionally in 364 adult subjects of both sexes. Results are mean Z scores ± SEM adjusted for age and sex. Only significant P values (measured by ANCOVA), with weight as covariate, within sexes are shown. The American Journal of Human Genetics 2004 74, 866-875DOI: (10.1086/420771) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 3 Differences in adult LS measurements, according to LRP5 haplotypes. aBMD, BMC, and bone area at the LS were measured cross-sectionally in men and women and were expressed as standardized Z scores (±SE). Haplotypes were based on SNPs c.1980, c.2047, c.3405, and c.4037, as detailed in table 3. Sizes for haplotype groups in adults of both sexes (panel A) are as follows: 0,0 n=156; 0,1 n=21; 0,2 n=50; 0,3 n=39; 2,1 n=4; 2,2 n=5; 3,1 n=2; 3,2 n=5; 3,3 n=2; 4,0 n=44; 4,1 n=5; 4,2 n=7; 4,3 n=4. Group sizes for the reduced haplotype combinations in female/male (females indicated by blackened circles; males indicated by unblackened squares) (panel B) are as follows: 0′,0′ (0′=2047G-4037C), n=133/112; 0′,3 (3=2047G-4037T), n=29/19; 0′,4 (4=2047A-4037T), n=31/27. P values for overall differences between haplotype groups were calculated by use of ANCOVA, with weight as a covariate. The American Journal of Human Genetics 2004 74, 866-875DOI: (10.1086/420771) Copyright © 2004 The American Society of Human Genetics Terms and Conditions

Figure 4 Changes in LS bone size and mass during childhood, according to LRP5 exon 9 c.2047 genotypes and haplotypes. Mean changes (±SEM) in LS BMC and projected area were evaluated between baseline and 1 year in prepubertal males (M) and females (F). Panel A shows mean changes according to c.2047 genotypes, panel B according to reduced haplotype combinations, as in figure 3B. The number of females/males in each group is as follows: 0′,0′, n=109/168; 0′,3, n=22/38; 0′,4, n=16/29. Significant P values for differences between exon 9 genotypes and between haplotypes 3 and 4 are shown. The American Journal of Human Genetics 2004 74, 866-875DOI: (10.1086/420771) Copyright © 2004 The American Society of Human Genetics Terms and Conditions