Bone mineral density loci specific to the skull portray potential pleiotropic effects on craniosynostosis.
Carolina Medina-GomezBenjamin H MullinAlessandra ChesiVid PrijateljJohn P KempChen Shochat-CarvalhoKaterina TrajanoskaCarol WangRaimo JoroTavia E EvansKatharina E SchrautRuifang Li-GaoTarunveer Singh AhluwaliaM Carola ZillikensKun ZhuDennis O Mook-KanamoriDaniel S EvansMaria NethanderMaria J KnolGudmar ThorleifssonIvana ProkicBabette S ZemelLinda BroerFiona E McGuiganNatasja M van SchoorSjur ReppeMikolaj A PawlakStuart H RalstonNathalie van der VeldeMattias LorentzonKari StefanssonHieab H H AdamsScott G WilsonMohammad Arfan IkramJohn P WalshTimo A LakkaKaare M GautvikJames F WilsonEric S OrwollCornelia M Van DuijnKlaus BønnelykkeAndre G UitterlindenUnnur StyrkársdóttirKristina E AkessonTimothy D SpectorJonathan H TobiasClaes OhlssonJanine F FelixHans BisgaardStruan F A GrantJohn Brent RichardsDavid M EvansBram C J van der EerdenJeroen van de PeppelCheryl L Ackert-BicknellDavid KarasikErika KagueFernando RivadeneiraPublished in: Communications biology (2023)
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.