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

Nature Genetics volume 44, pages 1360–1364 (2012)Cite this article

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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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  1. Cristina M Justice and Garima Yagnik: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Intramural Research, Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, US National Institutes of Health (NIH), Baltimore, Maryland, USA

    Cristina M Justice, Yoonhee Kim & Alexander F Wilson

  2. Department of Pediatrics, Section of Genetics, University of California Davis, Sacramento, California, USA

    Garima Yagnik, Jinoh Kim & Simeon A Boyadjiev

  3. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA

    Inga Peter, Ethylin Wang Jabs, Monica Erazo, Xiaoqian Ye, Edmond Ainehsazan & Lisong Shi

  4. Department of Pediatrics, Division of Craniofacial Medicine, University of Washington and Seattle Children's Research Institute, Seattle, Washington, USA

    Michael L Cunningham

  5. Department of Pediatrics, Division of Genetics, University of California Irvine, Irvine, California, USA

    Virginia Kimonis

  6. School of Women's and Children's Health, Sydney Children's Hospital, University of New South Wales, Sydney, New South Wales, Australia

    Tony Roscioli

  7. Craniofacial Unit, Oxford University Hospitals National Health Service Trust, John Radcliffe Hospital, Oxford, UK

    Steven A Wall & Andrew O M Wilkie

  8. Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK

    Andrew O M Wilkie

  9. Division of Genetics, Children's Hospital Boston, Harvard University, Boston, Massachusetts, USA

    Joan Stoler

  10. Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania, USA

    Joan T Richtsmeier & Yann Heuzé

  11. Department of Pathology and Pediatrics, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California, USA

    Pedro A Sanchez-Lara

  12. Department of Haematology and Genetics, South Eastern Area Laboratory Services, Sydney, New South Wales, Australia

    Michael F Buckley

  13. New York State Department of Health, Congenital Malformations Registry, Albany, New York, USA

    Charlotte M Druschel

  14. Division of Epidemiology, Department of Health and Human Services, Statistics and Prevention Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA

    James L Mills

  15. Division of Genetics, New York State Department of Health, Wadsworth Center, Albany, New York, USA

    Michele Caggana & Denise M Kay

  16. Department of Epidemiology, College of Public Health, University of Iowa, Iowa City, Iowa, USA

    Paul A Romitti

  17. Department of Otolaryngology, University of California Davis, Sacramento, California, USA

    Craig Senders

  18. Division of Plastic and Reconstructive Surgery, Kravis Children's Hospital, Mount Sinai Medical Center, New York, New York, USA

    Peter J Taub

  19. Department of Orofacial Sciences, University of California San Francisco, San Francisco, California, USA

    Ophir D Klein

  20. Department of Pediatrics, University of California San Francisco, San Francisco, California, USA

    Ophir D Klein

  21. Program in Craniofacial and Mesenchymal Biology, University of California San Francisco, San Francisco, California, USA

    Ophir D Klein

  22. Department of Neurological Surgery, University of California Davis, Sacramento, California, USA

    James Boggan & Marike Zwienenberg-Lee

  23. Department of Chemistry and Biochemistry, Medical University, Sofia, Bulgaria

    Cyrill Naydenov

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  1. Cristina M Justice
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  2. Garima Yagnik
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Contributions

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.

Corresponding author

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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