Absence of linkage for bone mineral density to chromosome 12q12-14 in the region of the vitamin D receptor gene

Polymorphisms in the region of the gene for the vitamin D receptor (VDR) (c hromosome 12q12-14) have been associated with differences in bone mineral d ensity (BMD) in some studies but not in others. Because linkage analysis as sesses allele sharing identical-by-descent among relatives instead of the a ssociation of a particular allele of an anonymous marker. we have performed a linkage study for bone BMD using microsatellite markers flanking the VDR locus. The present study explores whether or not relatives who share the c hromosomal region containing the VDR gene have more similar bone density. P articipants in the Framingham Osteoporosis Study (aged 37-89 years) who had undergone BMD testing were used to test for concordance of genotype with p henotype in the hip (femoral neck, Ward's area, trochanter) and lumbar spin e (L2-L4) with adjustment for covariates. Multipoint quantitative trait lin k age analysis using variance components methods was conducted with microsa tellite markers flanking the VDR locus (GATA91H06, GATA5A09, GGAT2G06) in 3 32 extended families containing 1062 individuals with both bone density mea sures and marker data. In addition, quantitative trait sib-pair linkage ana lysis, with a marker (AFM345xf1) in close proximity to the VDR locus, was p erformed in a second sample of 169 sibships (n = 413), comprising 284 full- sib pairs. Neither analysis revealed evidence for linkage of this region to femoral neck, Ward's area, lumbar spine, and trochanter in age or sex BMI, and height-adjusted bone density measures. Additional adjustment for alcoh ol intake, caffeine consumption, smoking status, and estrogen supplement (f emale only) did not alter the results. The present study could not demonstr ate linkage of BMD to chromosome 12q12-14. These findings suggest that neit her the VDR gene nor other genes at this locus are likely to have a substan tial impact upon bone density.