Significant association between body composition phenotypes and the osteocalcin genomic region in normative human population

Osteocalcin, a major inorganic component of bone matrix and marker of bone formation, is also involved in regulation of glucose and fat mass metabolism. However, much uncertainty remains about whether the above effect on fat mass has a genetic component. Our main aim was to test whether a variation of body composition phenotypes is associated with BGLAP genomic region variants. To achieve this aim, we used an ethnically homogeneous discovery sample of 230 families consisting of 1112 apparently healthy individuals (561 males and 551 females) of European origin. We conducted association analysis between six SNPs and five obesity-related phenotypes: plasma levels of leptin, anthropometrical fat mass (FM), principal component scores of eight skinfold (SK_PC) and nine circumference (CR_PC) measurements, and body mass index (BMI). Two powerful and robust tools were applied: the pedigree disequilibrium test and variance component models, taking into account both familial and genetic effects. Significant association results were observed for all phenotypes. The most significant results were observed between the haplotype composed of three SNPs (rs2758605-rs1543294-rs2241106) and BMI (p = 8.07− 7), and CR_PC (p = 5.29− 5). The association with BMI was tested and confirmed in our replication study, including 2244 unrelated adult US Caucasians, who were previously assessed for whole genome SNP data. In addition, we obtained an evidence of potential non-additive interactions between the above three SNPs concerning their association with BMI. Bioinformatics sources suggest that the aforementioned interaction could originate from different genetic loci in this region; however, ascertaining the exact circumstances requires a detailed molecular-genetic study.

► Osteocalcin circulating levels correlate with obesity and body composition. However, it is unknown whether these correlations have a genetic component.
► This study showed that there are significant associations between BGLAP genomic region variants and body mass‐related phenotypes.
► The most significant association between the haplotype composed of three SNPs and BMI was confirmed in our replication sample.
► We obtained an evidence of potential non-additive (epistatic) interactions between the above three SNPs concerning their association with BMI.
► The epistatic interaction found between the SNP alleles may be caused by read-through transcriptions of neighboring genes, PMF1 and BGLAP.