Mapping of quantitative ultrasound of the calcaneus bone to chromosome 1 by genome-wide linkage analysis

Quantitative ultrasound (QUS) may predict the risk of fracture independent of bone density. The aim of this study was to identify, using quantitative trait linkage analysis, chromosomal regions that might contain genes influencing variation in calcaneal ultrasound measures in a set of families from the general population. A genome-wide autosomal scan was conducted in 324 Caucasian families (1270 measured individuals) from the Framingham Osteoporosis Study, using a set of 401 Marshfield microsatellite markers with a 10 cM average density map. QUS measurements included broadband ultrasound attenuation (BUA), speed of sound (SOS), and quantitative ultrasound index (QUI). These phenotypes were regressed on age, age², body mass index, height, alcohol and caffeine consumption, smoking status, physical activity, and estrogen use in females, in each sex and generation separately. Adjusted QUS phenotypes demonstrated a strong heritability ranging from 0.45 (SOS) to 0.52 (BUA). By two-point variance components genome screening, phenotype-specific regions of possible linkage were identified on chromosomal regions lp36.3 and 5p15.2. The maximum LOD score attained was 2.74 for BUA with D1S468 (4 cM) and 2.69 for SOS with D5S817 (23 cM). QUI, a linear combination of the SOS and BUA, showed linkage with both markers (LOD = 2.1 with D1S468 and LOD = 2.2 with D5S817). Results of two-point analysis were confirmed by multipoint linkage analysis only for BUA, with LOD = 2.4 at D1S468, but not for SOS or QUI. The results for QUS, adjusted for femoral and lumbar spinal bone mineral density, in addition to the above covariates, were virtually the same. In conclusion, our results suggest that there may be genetic determinants for BUA on 1p36.3. These results should encourage further investigations of the genetic source of QUS variability and candidate polymorphisms in this region.