Bone, a major type of tissue in the human body, plays an important role in organism activity, such as protecting internal organs, maintaining body posture, and the motor system. Bone mineral density (BMD) is an essential determinant of bone strength and fracture risk. Bone size (BS) is another important factor influencing geometry and bone strength. Many recent studies have suggested that hip bone size could be a useful measurement to determine hip fracture risk. BS is predominantly determined by inheritance, with heritability as high as 75%.
Many genome-wide association studies (GWAS) and meta-analyses have been conducted for BMD. However, for BS, a limited number of GWAS has been conducted, leaving the specific genes underlying variation of BS largely unknown. Furthermore, the current GWAS and meta-analyses routinely analyze each trait. Joint consideration of correlated traits can provide additional information compared with information in individual traits and improve the ability to detect pleiotropic genes.
Researchers conducted a GWAS meta-analysis of hip bone mineral density (BMD) and hip bone size (BS) in 6,180 participants from five discovery samples and replicated in two large-scale samples. This study aimed to identify pleiotropic loci jointly regulating both traits. BMD and BS were measured at the proximal hip femur by dual-energy X-ray absorptiometry (DEXA) scan in the discovery phase, and estimated heel BMD were applied to the replication UKB sample used. Comparing the participants’ BMD and BS with their genetic data, SNPs from 2 genomic loci were significant at the genome-wide significance level in the discovery samples and were successfully replicated in the replication samples. One of the significant SNPs was rs7575512 near the ARL4C gene, showing an association with both BMD and BS. The ARL4C gene is tightly connected with Ribosomal Protein L31 (RPL31), and it has been reported to be associated with osteoporosis and lipid metabolism. In addition, rs7575512 is associated with Activin A Receptor Type 1B (ACVR1B) gene expression in macrophages, which was associated with abnormal bone structure in an experiment using a mouse model. In addition to that, five other genes showed a relationship with BS in the discovery samples.
Certain limitations exist in this study. One of these is that the discovery samples consist of five samples of diverse ancestries. It is well known that different ancestries may have different structures and genetic effects. There are also some potential limitations on how BMD was measured in the UKB sample. Read more about the study here:
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