Abstract
Our previous genome-wide association study (GWAS) for sagittal nonsyndromic craniosynostosis (sNCS) provided important insights into the genetics of midline CS. In this study, we performed a GWAS for a second midline NCS, metopic NCS (mNCS), using 215 non-Hispanic white case-parent triads. We identified six variants with genome-wide significance (P ≤ 5 × 10–8): rs781716 (P = 4.71 × 10–9; odds ratio [OR] = 2.44) intronic to SPRY3; rs6127972 (P = 4.41 × 10–8; OR = 2.17) intronic to BMP7; rs62590971 (P = 6.22 × 10–9; OR = 0.34), located ~ 155 kb upstream from TGIF2LX; and rs2522623, rs2573826, and rs2754857, all intronic to PCDH11X (P = 1.76 × 10–8, OR = 0.45; P = 3.31 × 10–8, OR = 0.45; P = 1.09 × 10–8, OR = 0.44, respectively). We performed a replication study of these variants using an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls; only the association for rs6127972 (P = 0.004, OR = 1.45; meta-analysis P = 1.27 × 10–8, OR = 1.74) was replicated. Our meta-analysis examining single nucleotide polymorphisms common to both our mNCS and sNCS studies showed the strongest association for rs6127972 (P = 1.16 × 10–6). Our imputation analysis identified a linkage disequilibrium block encompassing rs6127972, which contained an enhancer overlapping a CTCF transcription factor binding site (chr20:55,798,821–55,798,917) that was significantly hypomethylated in mesenchymal stem cells derived from fused metopic compared to open sutures from the same probands. This study provides additional insights into genetic factors in midline CS.
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Acknowledgements
The authors thank all families who contributed to this study. This project was supported by the: National Institute of Dental and Craniofacial Research (NIDCR)/National Institutes of Health (NIH) R01 DE016886 (S.A.B., P.A.R., A.C., K.B.); NIDCR/NIH DE018277 (M.L.C.); Centers for Disease Control and Prevention cooperative agreements under PA #96043, PA #02081, FOA #DD09-001, FOA #DD13-003, and NOFO #DD18-001 to the Centers for Birth Defects Research and Prevention participating in the National Birth Defects Prevention Study and/or the Birth Defects Study To Evaluate Pregnancy exposureS and the Iowa Center for Birth Defects Research and Prevention U01 DD001035 and U01 DD001223 (P.A.R.); Wellcome Investigator Award 102731 (A.O.M.W.); the Università Cattolica del Sacro Cuore (W.L.); and in part, by the Division of Intramural Research Program of the National Human Genome Research Institute, NIH (C.M.J., J.A.S., A.F.W.). Additional support was provided by the Intramural Research Program, National Institute of Child Health and Human Development, NIH: HHSN275201100001I, HHSN27500005. We thank Samantha Edwards, Gill Roberts, Danielle Stevenson, Vivienne Sutton, Elizabeth Tidey, Paolo Frassanito, Luca Massimi and Massimo Caldarelli for help with specimen collection. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268200782096C. The findings and conclusions in the report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
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Justice, C.M., Cuellar, A., Bala, K. et al. A genome-wide association study implicates the BMP7 locus as a risk factor for nonsyndromic metopic craniosynostosis. Hum Genet 139, 1077–1090 (2020). https://doi.org/10.1007/s00439-020-02157-z
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DOI: https://doi.org/10.1007/s00439-020-02157-z