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

Cristina M Justice ,Lisong Shi,Yoonhee Kim,Xiaoqian Ye,Cyrill Naydenov,Edmond Ainehsazan,Ethylin Wang Jabs,Inga Peter,Tony Roscioli,Marike Zwienenberg-Lee,Garima Yagnik,Yann Heuzé,Virginia Kimonis,Peter J Taub ,Steven A Wall ,Joan T Richtsmeier ,Michael L Cunningham ,Michael F Buckley ,Craig W Senders ,Paul A Romitti ,James E Boggan ,Ophir D Klein ,Alexander F Wilson ,James L Mills ,Joan M Stoler ,Andrew O.m Wilkie ,Charlotte M Druschel ,Denise M Kay ,Jin Oh Kim ,Mónica Erazo ,Pedro A Sanchez‐Lara ,Michèle Casini ,Simeon A Boyadjiev

doi:10.1038/ng.2463

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.

Highlights

Skull development is a complex process that involves ongoing inter action between the bones of the skull and cranial soft tissues
80% of craniosynostosis occurs as an iso lated anomaly, called nonsyndromic craniosynostosis (NSC), with out major associated malformations[1]
Rare mutations in the FGFR2, TWIST1, FREM1, LRIT3, EFNA4 and RUNX2 duplications have been reported in a minor fraction of individuals with NSC2–9

Summary

Introduction

Skull development is a complex process that involves ongoing inter action between the bones of the skull and cranial soft tissues. The 18 SNPs on chromosome 20 were in two for the replication study (Supplementary Table 2). Except for a predicted mRNA, BC038533, we did markers on chromosome 20 and four out of the five markers on 7p14.3 not identify any other known genes, copy number variants, tran (with one SNP failing genotyping) were successfully replicated with scripts, microRNAs or regulatory elements in this region.

Results

Conclusion