A GWAS identifies susceptibility loci for nonsyndromic sagittal craniosynostosis(sNSC) near BMP2 and within BBS9

Nitesh Turaga
June 25th 2014

Introduction

(from cranio, cranium; + syn, together; + ostosis relating to bone)

  • Craniosynostosis is a condition in which one or more of the fibrous sutures in an infant skull prematurely fuses by turning into bone (ossification), thereby changing the growth pattern of the skull.
  • Saggital craniosynostosis is the most common phenotype of this condition.
  • 80% occurs as an isolated anomaly, hence called NSC (nonsyndromic craniosynostosis) : No associated malformations.
  • sNSC: nonsyndromic sagittal craniosynostosis

Study Design

  • 201 case-parent trios and 13 nuclear families with sNSC. Total : 214
  • 68% NHW (European Non-hispanic white)
  • 32% mixed ehnicity families
  • Samples were genotyped on Illumina 1M Human Omni1-Quad array.

PCA with EigenSoft

  • Confirm ancestry with PCA using the EIGENSOFT 3.0
  • This reduces sample size to 130 samples from 214.

Quality Control

  • After QC, retained 915307 SNPs.

  • Using the TDT, (Tranmission Disequilibrium test) identify 21 SNPs, which have a base threshold p-value of \( 5*10^{-8} \)

  • 18 SNPs on Chromosome 20

  • 3 SNPs on Chromosome 7

Shown in Fig 1

Manhattan plot of P-values (Fig 1)

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18 SNPs on CHR 20, two Linkage disequilibrium blocks

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3 SNPs on CHR 7, no blocks,

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Regional Association plots

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  • Most significant SNP, rs1884302 is located 345kb downstream of BMP2
  • 3 SNPs, span 167kb within BBS9.

Table 1

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  • Replication study: 104 NHW trios with a male proband(male is affected)
  • Meta Analysis : 172 unrelated cases, 548 unaffected controls

References

  • 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. A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9. Nat Genet. 2012 Dec;44(12):1360-4. doi: 10.1038/ng.2463. Epub 2012 Nov 18. PubMed PMID: 23160099; PubMed Central PMCID: PMC3736322.

  • Kimonis, V. et al. Genetics of craniosynostosis. Semin. Pediatr. Neurol. 14, 150–161 (2007).