Genes influencing variation in serum osteocalcin concentrations are linkedto markers on chromosomes 16q and 20q

Osteocalcin (OC) is an important constituent of bone that is synthesized by osteoblasts. Serum levels of OC have been used as a biochemical marker of bone turnover. To identify the genes influencing variation in serum OC leve ls, we conducted a genome-wide scan in 424 individuals comprising 10 large multigenerational families. OC levels were measured by immunoassay, and gen etic markers mere typed at approximately 10-cM intervals across the genome. Quantitative trait linkage was tested using a multipoint analysis based on variance component methodology, adjusting for the effects of age, sex, and oral contraceptive use. Significance levels for linkage were obtained empi rically, by Monte Carlo simulation. The heritability of OC levels in this p opulation was 62 +/- 8%. We detected significant evidence for linkage betwe en a quantitative trait locus influencing serum OC levels and markers on ch romosome 16q, and suggestive evidence for linkage of OC levels with markers on chromosome 20q. The multipoint lod scores peaked at 3.35 on chromosome 16 and 2.78 on chromosome 20, corresponding to P values of 0.00004 and 0.00 017, respectively. A potential candidate gene for bone formation in the lin ked region on chromosome 20 is CDMP1, which encodes cartilage-derived morph ogenetic protein I. Future studies should evaluate whether variation in CDM P1 or in other genes in the linked regions on chromosomes 16 and 20 influen ce the rate of bone turnover.