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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.

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Figure 1: Manhattan plot of the P values obtained from the genome-wide TDT of 130 trios (N = 914,402).
Figure 2: Regional association plots for associations with sNSC at genome-wide significance.

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Acknowledgements

The authors thank all families who contributed to this study. S.A.B. is partially funded through a Children's Miracle Network Endowed Chair and through grants K23 DE00462, R03 DE016342 and R01 DE016886 from the National Institute of Dental and Craniofacial Research (NIDCR)/NIH and M01-RR00052 from the National Center for Research Resources/NIH and was fully supported by Zlatka, Anton and Alec Boyadjiev. Partial funding was also obtained from grants to E.W.J. (US Centers for Disease Control and Prevention (CDC) 5 R01 DD000350), M.L.C. (R01 DE018227), A.O.M.W. (Wellcome Trust 093329), P.A.R. (CDC 5U01DD000492), J.K. (NIDCR/NIH R21DE022419), J.L.M. (Intramural Research Program (IRP) of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); IRP HHSN267200703431C; NICHD N01-DK-7-3431), P.A.S.-L. (Robert Wood Johnson Foundation 3R37DE012711-13S1 and Children's Hospital Los Angeles–University of Southern California Child Health Research Career Development Program; NIH K12-HD05954), J.T.R. (NIDCR/NIH and the American Recovery and Reinvestment Act R01 DE018500 and 3R01 DE018500-02S1) and I.P. (National Center for Advancing Translational Sciences, NIH UL1TR000067). This project was also supported in part by the Division of Intramural Research Program of the National Human Genome Research Institute, NIH (C.M.J., Y.K. and A.F.W.). Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to Johns Hopkins University, contract number HHSN268200782096C. We thank B. Wilson, N. Issac, C. Nauta, E. Goude, E. Cherkez, L. Peters and J. Harrison for patient recruitment, C. Boehm and A. Scott for coordination of discovery-phase genotyping, C. Stevens, A. Stoner, J.L. Liu, A. Gearhart, A. Atkins and E. McGrath for bench work, D. Mortlock for bioinformatic analysis and informative discussion and J. Graham (Cedars-Sinai Hospital, Los Angeles, California, USA), J. Bernstein (Stanford University, Palo Alto, California, USA), J. Marsh (Washington University, St. Louis, Missouri, USA), J. Panchal (University of Oklahoma Health Science Center, Oklahoma, USA), T. Tollefson (University of California Davis, Sacramento, California, USA) and M. Passos-Bueno (University of São Paolo, Brazil) for contributing clinical information and biospecimens for this project.

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C.M.J. and G.Y. are the first coauthors of the manuscript. C.M.J., Y.K. and I.P. performed statistical analyses. G.Y., M.E., X.Y., E.A. and L.S. performed experiments. C.M.J., G.Y., Y.K., I.P., M.L.C., V.K., T.R., A.O.M.W., J.S., J.T.R., Y.H., P.A.S.-L., M.F.B., J.K., A.F.W. and S.A.B. analyzed data. C.M.J. and G.Y. wrote the manuscript, with contributions from Y.K., I.P., J.T.R., Y.H., P.A.R., A.F.W. and S.A.B. E.W.J., M.L.C., V.K., S.A.W., J.S., P.A.S.-L., M.F.B., C.M.D., J.L.M., M.C., P.A.R., D.M.K., C.S., P.J.T., O.D.K., J.B., M.Z.-L. and C.N. contributed materials and reagents. E.W.J., A.O.M.W., M.F.B., D.M.K. and P.J.T. contributed to editing of the manuscript. E.W.J., C.M.D., J.L.M., M.C., P.A.R., D.M.K., C.S., P.J.T., O.D.K., J.B., M.Z.-L. and C.N. helped with experimental design. J.K. and A.F.W. supervised the research. S.A.B. was the principal investigator, designed and supervised research and recruited and evaluated participants.

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Correspondence to Simeon A Boyadjiev.

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Justice, C., Yagnik, G., Kim, Y. et al. A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat Genet 44, 1360–1364 (2012). https://doi.org/10.1038/ng.2463

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