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A Genome-Wide Association Study Identifies Two Candidate Genes for Nonsyndromic Sagittal Craniosynostosis

January 2013

Background: Craniosynostosis results from premature fusion of one or more cranial sutures. In most instances, craniosynostosis occurs with no other major malformations (nonsyndromic craniosynostosis, NSC). Rare genetic variants in a few genes have been associated with NSC, occurring in a small proportion of individuals with NSC. Sagittal craniosynostosis is the most common type of NSC. These investigators aimed to identify genomic regions that affect susceptibility to nonsyndromic sagittal craniosynostosis (sNSC); published literature suggests that both genetic environmental factors affect development of sNSC, but little is known about specific genes that may be involved. They conducted a genome-wide search in 214 families with at least one individual with sNSC; genotyping was done on the Illumina 1M Human Omni1-Quad array (one million single nucleotide polymorphisms or SNPs). The analyses focused on 130 case-parent trios of non-Hispanic white (NHW) ancestry, using a strict definition of sNSC. A replication study, in an independent study population that included 172 NHW unrelated individuals with sNSC (cases) and 548 without (controls), was conducted for verification of promising results from the genome-wide search.

Advance: The genome-wide search yielded two regions with statistically significant results, chromosome regions 7p14.3 (three SNPs in a region spanning two BBS9 [Bardet-Biedl syndrome 9] introns) and 20p12.3 (18 SNPs in two linkage disequilibrium blocks, most significant SNP near BMP2 [bone morphometric protein 2]); follow-up exome sequencing studies did not identify any genetic variants predicted to be harmful. For the replication study, 25 SNPs that met genome-wide significance or were suggestive (P < 10-5) were genotyped in the case-control group. SNPs in the two regions that reached genome-wide significance in the initial results, 7p14.3 and 20p12.3, were significant in the combined analyses. These SNPs are near two genes involved in skeletal development (BBS9 and BMP2).

Public Impact/Significance: This genome-wide search and replication study identified two biologically-plausible candidate genes for development of sNSC. Further research to identify the reasons for the significant associations and how these genes may affect development of cranial sutures may lead to insights into the development of craniosynostosis.

Publication Citation: Justice CM, Yagnik G, Kim Y, Peter I, Jabs EW, Erazo M, Ye X, Ainehsazan E, Shi L, Cunningham ML, Kimonis V, Roscioli T, Wall SA, Wilkie AO, Stoler J, Richtsmeier JT, Heuzé Y, Sanchez-Lara PA, Buckley MF, Druschel CM, Mills JL, Caggana M, Romitti PA, Kay DM, Senders C, Taub PJ, Klein OD, Boggan J, Zwienenberg-Lee M, Naydenov C, Kim J, Wilson AF, Boyadjiev SA (2012). A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat Genet, Nov 18. doi: 10.1038/ng.2463. [Epub ahead of print]. Link to PDF Article

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This page last updated: January 06, 2014