Variance component linkage analysis indicates a QTL for femoral neck bone mineral density on chromosome 1p36

Osteoporosis is a common condition characterized by reduced skeletal streng th and increased susceptibility to fracture. Eight million Americans over t he age of 50 have osteoporosis of the femoral neck. The most important risk factor for osteoporosis is low bone mineral density (BMD), and several epi demiological studies have shown the importance of genetic factors in determ ining variability of BMD. An initial genome screen in seven large pedigrees suggested that a candidate region conferring susceptibility to low BMD of the femoral neck was located on chromosome 1p36. We have now confirmed and extended this finding by analyzing nine microsatellite markers spanning a 4 0 cM interval across the candidate region in an expanded sample of 42 famil ies. Heritability of femoral neck BMD was estimated as 0.51 +/- 0.13 in the se families, after accounting for the effects of age, sex, body mass index, height and weight. Variance component linkage analysis yielded a maximum m ultipoint LOD score of 3.53 for linkage of femoral neck BMD to a quantitati ve trait locus (QTL) located near marker D1S214. The associated empirical P -value by simulation analysis was equal to 0.0001. The results strongly sup port the hypothesis that a major QTL controlling femoral neck BMD is locate d on chromosome 1p36.2-p36.3, and further analysis of candidate genes in th is region is warranted.