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

Abstract

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.

GWAS of ∼30,000 samples with bone mineral density at multiple skeletal sites and its clinical relevance on fracture prediction, genetic correlations and prioritization of drug targets

“…It should be noted that QUS-derived BMD primarily reflected the bone mass at the heel calcaneus and exhibited limited correlation (0.5~0.65) with DXA-derived BMD at the spine and hip 21 . Additionally, we confirmed the ZIC1/ZIC4 locus for head BMD (P=2.19×10 -8 ) which was reported in a very recently GWAS meta-analysis 22 .…”

Valid inference for machine learning-assisted GWAS

“…DXA-BMD is the best indicator and primary diagnostic marker for osteoporosis and fracture risk in the clinic [30][31][32] . It also enables studying the site-specific genetic architecture of BMD which may lead to more accurate assessment of fracture risk in different parts of the skeleton [33][34][35][36][37] . However, DXA-BMD is currently only measured in around 10% of UKB participants.…”

“…We performed sample overlap correction implemented in METAL for head and total body BMD due to the overlap of a small subset of UKB individuals in our analysis and published GWAS. Novel BMD loci were defined as genome-wide significant POP-GWAS loci that are not in LD with six previous BMD GWAS 30,31,35,42,43 (tag-r2 0.01 and tag-kb 100).…”

GWAS-informed data integration and non-coding CRISPRi screen illuminate genetic etiology of bone mineral density

“…Unsurprisingly, given the known key role of osteoblasts in BMD determination, among the significant enrichments for BMD were several for primary osteoblasts as well as the hFOB and BMP2-stimulated human mesenchymal stem cell models (hMSC-osteoblasts) previously employed by ourselves 31,34,37,38 and others [39][40][41] to interrogate the genetic etiology of BMD in an osteoblast context. Specifically, we observed significant enrichment in primary-osteoblast H3K4me1 (adj.…”