To date many genetic variants that account for a small proportion of the variance in BMD have been identified by large-scale genome-wide association studies (GWAS), using adult BMD measurements of hip and spine. Additional BMD loci have been identified using other techniques such as heel ultrasound and peripheral quantitative computed tomography (pQCT). In contrast to hip and spine BMD, skull BMD is non-weight bearing and hence as trait in GWAS of particular interest because it is less influenced by the environment. Skull BMD is also relevant with osteoporosis outcomes and the specific loci allow insight into key genes in bone biology, particularly to intramembranous ossification. Intramembranous bones are predominant in the head, forming the cranial vault and face.
Medina-Gomez et al. have recently published in Communications Biology the outcomes of a meta-analysis of a large-scale GWAS in non-pediatric populations comprising up to 43,800 individuals focusing specifically on the BMD variation of the skull. The analysis has identified 59 loci explaining 12.5% of the trait variance. The study highlights four novel loci associated to skull BMD (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3). For functional analysis into craniofacial development, zebrafish are particularly suitable as they allow non-invasive in vivo analysis of skull and sutures during their formation. The zebrafish models provided evidence for the implication of these newly identified genes in the mineralization of the skull and a zebrafish crispant models demonstrated the importance of these genes in the pathophysiology of craniosynostosis, in particular in calvaria growth and abnormal suture patterning.
Additionally, prkar1a knockout models developed asymmetric bone growth and elevated BMD implicating that genes affecting skull development may at least partially also regulate BMD of the axial skeleton. In summary, this large-scale international GWAS of skull BMD provides new insight into the pathophysiology, diagnosis and potential treatment of skeletal diseases.
Medina-Gomez, C., Mullin, B.H., Chesi, A. et al. Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis. Commun Biol 6, 691 (2023). https://doi.org/10.1038/s42003-023-04869-0