rs10262453 (BBS9): Sagittal Craniosynostosis Risk

Key takeaways

• rs10262453 lies within the BBS9 gene on chromosome 7p14.3 and is one of the strongest genetic signals identified for non-syndromic sagittal craniosynostosis.
• Sagittal craniosynostosis is the premature fusion of the skull's top suture, affects about 1 in 5,000 newborns, and accounts for 40-58% of all craniosynostosis cases.
• The minor allele showed a large protective effect (OR = 0.19), replicated in two independent cohorts with p-values well below genome-wide significance.
• BBS9 plays a role in skeletal development, but the mechanism connecting it to premature skull suture closure is not yet known.
• GTEx data show the alt allele increases BBS9 expression across multiple brain regions and peripheral nerve tissue.

What the research says rs10262453 lies within a 167 kb region spanning introns 4 and 15 of BBS9 (Bardet-Biedl Syndrome 9, chromosome 7p14.3). A genome-wide association study (GWAS) - a method that simultaneously scans hundreds of thousands of genetic markers to identify trait-associated variants - found this SNP (single-nucleotide polymorphism, a one-letter variation in the DNA code) significantly associated with non-syndromic sagittal craniosynostosis (sNSC), the premature closure of the sagittal suture (the fibrous seam running front-to-back along the top of the skull), a condition affecting roughly 1 in 5,000 newborns. The discovery phase used 130 non-Hispanic white (NHW) case-parent trios (P = 1.61 × 10^-¹^0; OR = 0.19), and the association was independently replicated in 172 unrelated sNSC probands and 548 controls (P = 3.50 × 10^-¹^4). RT-PCR resequencing of BBS9 in calvarial (skull-cap) osteoblast cell lines from eight sNSC patients identified six variants in the gene, all assessed as benign by bioinformatic tools, leaving the precise causal mechanism unresolved.

Reported associations

• Non-syndromic sagittal craniosynostosis (discovery): The minor allele at this locus was associated with markedly reduced odds of sNSC (OR = 0.19, P = 1.61 × 10^-¹^0) in 130 NHW case-parent trios; the flanking SNP rs17724206 showed a similar protective direction (OR = 0.22, P = 1.50 × 10^-8) within the same 167 kb BBS9 region.
• Non-syndromic sagittal craniosynostosis (independent replication): The association was confirmed in 172 unrelated sNSC probands and 548 controls (P = 3.50 × 10^-¹^4), consistent in both direction and magnitude.

Evidence quality The discovery cohort comprised 130 NHW case-parent trios analyzed by the transmission disequilibrium test (TDT), a family-based method assessing whether a variant is transmitted to affected children more often than chance predicts. Replication used a fully independent sample of 172 probands and 548 controls, both stages restricted to non-Hispanic white participants - limiting generalizability to other ancestries. The genome-wide significance threshold (P < 5 × 10^-8) was exceeded at discovery, and the replication p-value (3.50 × 10^-¹^4) substantially strengthens confidence in the signal. The OR of 0.19 is unusually large for a common-variant GWAS finding. No conflicting evidence is present within the provided studies, but the evidence base consists of a single published GWAS; no additional independent replication studies are included here. No coding mutations with obvious functional consequences were identified in BBS9 resequencing, so the mechanistic basis of the association remains open.

Tissue-specific expression effects

• BBS9: The alt allele at rs10262453 is associated with increased BBS9 expression across eight tissues, most prominently in brain regions - cervical spinal cord, substantia nigra, putamen, frontal cortex (BA9), cortex, and caudate (the latter three all basal ganglia structures) - as well as the pituitary gland and tibial nerve. GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.