Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis.

Medina-Gomez C, Mullin BH, Chesi A, Prijatelj V, Kemp JP, Shochat-Carvalho C, Trajanoska K, Wang C, Joro R, Evans TE, Schraut KE, Li-Gao R, Ahluwalia TS, Zillikens MC, Zhu K, Mook-Kanamori DO, Evans DS, Nethander M, Knol MJ, Thorleifsson G, Prokic I, Zemel B, Broer L, McGuigan FE, van Schoor NM, Reppe S, Pawlak MA, Ralston SH, van der Velde N, Lorentzon M, Stefansson K, Adams HHH, Wilson SG, Ikram MA, Walsh JP, Lakka TA, Gautvik KM, Wilson JF, Orwoll ES, van Duijn CM, Bønnelykke K, Uitterlinden AG, Styrkársdóttir U, Akesson KE, Spector TD, Tobias JH, Ohlsson C, Felix JF, Bisgaard H, Grant SFA, Richards JB, Evans DM, van der Eerden B, van de Peppel J, Ackert-Bicknell C, Karasik D, Kague E, Rivadeneira F

Commun Biol 6 (1) 691 [2023-07-04; online 2023-07-04]

Skull bone mineral density (SK-BMD) provides a suitable trait for the discovery of key genes in bone biology, particularly to intramembranous ossification, not captured at other skeletal sites. We perform a genome-wide association meta-analysis (n ~ 43,800) of SK-BMD, identifying 59 loci, collectively explaining 12.5% of the trait variance. Association signals cluster within gene-sets involved in skeletal development and osteoporosis. Among the four novel loci (ZIC1, PRKAR1A, AZIN1/ATP6V1C1, GLRX3), there are factors implicated in intramembranous ossification and as we show, inherent to craniosynostosis processes. Functional follow-up in zebrafish confirms the importance of ZIC1 on cranial suture patterning. Likewise, we observe abnormal cranial bone initiation that culminates in ectopic sutures and reduced BMD in mosaic atp6v1c1 knockouts. Mosaic prkar1a knockouts present asymmetric bone growth and, conversely, elevated BMD. In light of this evidence linking SK-BMD loci to craniofacial abnormalities, our study provides new insight into the pathophysiology, diagnosis and treatment of skeletal diseases.

Clinical Genomics Gothenburg [Collaborative]

PubMed 37402774

DOI 10.1038/s42003-023-04869-0

Crossref 10.1038/s42003-023-04869-0

pmc: PMC10319806
pii: 10.1038/s42003-023-04869-0