Human Genetics

, Volume 132, Issue 7, pp 771–781 | Cite as

Confirming genes influencing risk to cleft lip with/without cleft palate in a case–parent trio study

  • T. H. Beaty
  • M. A. Taub
  • A. F. Scott
  • J. C. Murray
  • M. L. Marazita
  • H. Schwender
  • M. M. Parker
  • J. B. Hetmanski
  • P. Balakrishnan
  • M. A. Mansilla
  • E. Mangold
  • K. U. Ludwig
  • M. M. Noethen
  • M. Rubini
  • N. Elcioglu
  • I. Ruczinski
Original Investigation

Abstract

A collection of 1,108 case–parent trios ascertained through an isolated, nonsyndromic cleft lip with or without cleft palate (CL/P) was used to replicate the findings from a genome-wide association study (GWAS) conducted by Beaty et al. (Nat Genet 42:525–529, 2010), where four different genes/regions were identified as influencing risk to CL/P. Tagging SNPs for 33 different genes were genotyped (1,269 SNPs). All four of the genes originally identified as showing genome-wide significance (IRF6, ABCA4 and MAF, plus the 8q24 region) were confirmed in this independent sample of trios (who were primarily of European and Southeast Asian ancestry). In addition, eight genes classified as ‘second tier’ hits in the original study (PAX7, THADA, COL8A1/FILIP1L, DCAF4L2, GADD45G, NTN1, RBFOX3 and FOXE1) showed evidence of linkage and association in this replication sample. Meta-analysis between the original GWAS trios and these replication trios showed PAX7, COL8A1/FILIP1L and NTN1 achieved genome-wide significance. Tests for gene–environment interaction between these 33 genes and maternal smoking found evidence for interaction with two additional genes: GRID2 and ELAVL2 among European mothers (who had a higher rate of smoking than Asian mothers). Formal tests for gene–gene interaction (epistasis) failed to show evidence of statistical interaction in any simple fashion. This study confirms that many different genes influence risk to CL/P.

Supplementary material

439_2013_1283_MOESM1_ESM.docx (2.5 mb)
Supplementary material 1 (DOCX 2589 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • T. H. Beaty
    • 1
  • M. A. Taub
    • 2
  • A. F. Scott
    • 3
  • J. C. Murray
    • 4
  • M. L. Marazita
    • 5
  • H. Schwender
    • 8
  • M. M. Parker
    • 1
  • J. B. Hetmanski
    • 1
  • P. Balakrishnan
    • 1
  • M. A. Mansilla
    • 4
  • E. Mangold
    • 6
  • K. U. Ludwig
    • 6
    • 7
  • M. M. Noethen
    • 6
    • 7
  • M. Rubini
    • 9
  • N. Elcioglu
    • 10
  • I. Ruczinski
    • 2
  1. 1.Department of Epidemiology, School of Public HealthJohns Hopkins UniversityBaltimoreUSA
  2. 2.Department of Biostatistics, School of Public HealthJohns Hopkins UniversityBaltimoreUSA
  3. 3.Institute of Genetic Medicine, School of MedicineJohns Hopkins UniversityBaltimoreUSA
  4. 4.Department of Pediatrics, School of MedicineUniversity of IowaIowa CityUSA
  5. 5.Department of Oral Biology, Center for Craniofacial and Dental Genetics, School of Dental MedicineUniversity of PittsburghPittsburghUSA
  6. 6.Institute of Human GeneticsUniversity of BonnBonnGermany
  7. 7.Department of Genomics, Life and Brain CenterUniversity of BonnBonnGermany
  8. 8.Mathematical InstituteHeinrich-Heine-University DuesseldorfDuesseldorfGermany
  9. 9.Medical Genetics Unit, Department of Biomedical and Special Surgery SciencesUniversity of FerraraFerraraItaly
  10. 10.Department of Pediatric Genetics, School of MedicineMarmara UniversityIstanbulTurkey

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