A genome-wide linkage scan for low spinal bone mineral density in a single extended family confirms linkage to 1p36.3.

Osteoporotic fractures are an increasing cause of mortality and morbidity in ageing populations. A major risk determinant for these fractures is bone mineral density (BMD). Variation on BMD is thought, on the basis of twin and family studies, to be subject to a large amount of genetic variation and it has been hypothesised that this may be due to the influence of multiple genes. However, in families showing segregation of low or high BMD, single major genes have been shown to play a crucial role. We performed a genome-wide screen using 380 microsatellite markers in a single extended family (n=34) in which early-onset low spinal areal BMD segregates in an autosomal dominant-like fashion. A two-point linkage analysis was performed, revealing a maximum LOD score of 3.07 on 1p36.3 (D1S468), confirming results of previous linkage studies of BMD, while no other suggestive linkage peaks (LOD>2.2) were detected elsewhere in the genome. Microsatellite markers were subsequently genotyped for a +/-6.9 Mb region surrounding D1S468. This revealed critical recombination events restricting the candidate region to 1.2 Mb and 19 genes. Sequencing analysis of the coding region of candidate genes WDR8 and EGFL3 revealed no mutations or disease-associated polymorphisms. Our results provide some evidence supporting the hypothesis that there are genetic determinants for spinal BMD on 1p36.3. Although no specific disease causing mutation has yet been found, the delineation of a relatively small candidate region in a single extended family opens perspectives to identify a major gene for spinal BMD.