Exclusion mapping of chromosomes 1, 4, 6 and 14 with bone mineral density in 79 Caucasian pedigrees

Low bone mineral density (BMD) is a major determinant of osteoporosis and is under strong genetic control. A large number of linkage and association studies for BMD variation have been conducted, with the results being largely inconsistent. Linkage exclusion analysis is a useful tool for gene mapping but has never been used on BMD. In the present study, we conducted a linkage exclusion mapping for BMD variation on chromosomes 1, 4, 6 and 17 in 79 Caucasian pedigrees. For hip BMD variation, several genomic regions were excluded for effect sizes of 10% or greater, including regions of 61-77 cM at 1p35-p34, 167-196 cM at 1q21-q23 and 261-291 cM at 1q42-q44; 85-112 cM at 4q21-q25 and 146-150 cM at 4q31; and 77-85 cM at 6p12-q13. For spine BMD, we were able to exclude the regions of 168-189 cM at 1q21-q23, 92-94 cM at 4q21 and 106-107 cM at 4q24 and 56-103 cM at 17q12-q25, as having effect sizes of 10% or greater. These results suggest that a number of candidate genes located in the excluded regions, such as interleukin 6 receptor (IL6R) gene, type I collagen alpha 1 (COL1A1) gene and bone morphogenetic protein-3 (BMP3) gene are unlikely to have a substantial effect on BMD variation in this Caucasian population. Along with previous studies searching for genes underlying BMD variation, the current study has further delineated the genetic basis of BMD variation and provided valuable information for future genetic studies.