LINKAGE OF A GENE CAUSING HIGH BONE MASS TO HUMAN-CHROMOSOME-11 (11Q12-13)

The purpose of this paper is to report the linkage of a genetic locus (designated ''HBM'') in the human genome to a phenotype of very high s pinal bone density, using a single extended pedigree. We measured spin al bone-mineral density, spinal Z(BMD), and collected blood from 22 me mbers of this kindred. DNA was genotyped on an Applied Biosystems mode l 377 (ABI PRISM Linkage Mapping Sets; Perkin Elmer Applied Biosystems ), by use of fluorescence-based marker sets that included 345 markers. Both two-point and multipoint linkage analyses were performed, by use of affected/unaffected and quantitative-trait models. Spinal Z(BMD) f or affected individuals (N = 12) of the kindred was 5.54 +/- 1.40; and for unaffected individuals (N = 16) it was 0.41 +/- 0.81. The trait w as present in affected individuals 18-86 years of age, suggesting that HEM influences peak bone mass. The only region of linkage was to a se ries of markers on chromosome 11 (11q12-13). The highest LOD score (5. 21) obtained in two-point analysis, when a quantitative-trait model wa s used, was at D11S987. Multipoint analysis using a quantitative-trait model confirmed the linkage, with a LOD score of 5.74 near marker D11 S387. HEM demonstrates the utility of spinal Z(BMD) as a quantitative bone phenotype that can be used for linkage analysis. Osteoporosis pse udoglioma syndrome also has been mapped to this region of chromosome 1 1. Identification of the causal gene for both traits will be required for determination of whether a single gene with different alleles that determine a wide range of peak bone densities exists in this region.