A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9

Abstract

Sagittal craniosynostosis is the most common form of craniosynostosis, affecting approximately one in 5,000 newborns. We conducted, to our knowledge, the first genome-wide association study for nonsyndromic sagittal craniosynostosis (sNSC) using 130 non-Hispanic case-parent trios of European ancestry (NHW). We found robust associations in a 120-kb region downstream of BMP2 flanked by rs1884302 (P = 1.13 × 10(-14), odds ratio (OR) = 4.58) and rs6140226 (P = 3.40 × 10(-11), OR = 0.24) and within a 167-kb region of BBS9 between rs10262453 (P = 1.61 × 10(-10), OR = 0.19) and rs17724206 (P = 1.50 × 10(-8), OR = 0.22). We replicated the associations to both loci (rs1884302, P = 4.39 × 10(-31) and rs10262453, P = 3.50 × 10(-14)) in an independent NHW population of 172 unrelated probands with sNSC and 548 controls. Both BMP2 and BBS9 are genes with roles in skeletal development that warrant functional studies to further understand the etiology of sNSC.

Figures

Figure 1. Manhattan plot of P-values obtained from the genome-wide TDT of 130 trios (N=914,402)

The x-axis corresponds to the genomic position of the autosomes, while the y-axis is the −log10 of the P-value. Horizontal dashed line corresponds to the genome-wide significance threshold of P ≤ 5 × 10−8.

Figure 2. Regional association plots for associations with sNSC at genome-wide significance

Upper panel: P-values (-log10) of the GWAS (solid circle), replication (triangle) and meta-analysis (asterisk) on the y-axis are plotted against the genomic positions of each SNP on the x-axis on (a) chromosome 20 and on (b) chromosome 7. Horizontal dashed line corresponds to the genome-wide significance threshold of P ≤ 5 × 10−8. Genes in region are depicted below (not to scale). The LD (r2) between the lead SNP and other SNPs are indicated in different colors. The blue lines indicate the recombination rates in cM per Mb using HapMap controls. Lower panel: LD plots (based on r2 value) using genotyped subjects from the GWAS study.

Figure 2. Regional association plots for associations with sNSC at genome-wide significance

Upper panel: P-values (-log10) of the GWAS (solid circle), replication (triangle) and meta-analysis (asterisk) on the y-axis are plotted against the genomic positions of each SNP on the x-axis on (a) chromosome 20 and on (b) chromosome 7. Horizontal dashed line corresponds to the genome-wide significance threshold of P ≤ 5 × 10−8. Genes in region are depicted below (not to scale). The LD (r2) between the lead SNP and other SNPs are indicated in different colors. The blue lines indicate the recombination rates in cM per Mb using HapMap controls. Lower panel: LD plots (based on r2 value) using genotyped subjects from the GWAS study.