Genome-wide association study identifies new disease loci for isolated clubfoot

J Med Genet. 2014 May;51(5):334-9. doi: 10.1136/jmedgenet-2014-102303. Epub 2014 Mar 25.


Background: Clubfoot is a common congenital birth defect with complex inheritance patterns. Currently, the genetic and morphological basis of clubfoot is poorly understood. To identify genetic risk factors associated with clubfoot, we performed a genome-wide association study of common genetic variants.

Methods: The DNA of 396 isolated clubfoot patients and 1000 controls of European descent was genotyped for >600 000 single nucleotide polymorphisms (SNP) using the Affymetrix 6.0 array. Replication was performed with an independent cohort of 370 isolated clubfoot cases and 363 controls of European descent.

Results: Strongest evidence for an association of clubfoot was found with an intergenic SNP on chromosome 12q24.31 between NCOR2 and ZNF664 (rs7969148, OR=0.58, p=1.25×10⁻⁵) that was significant on replication (combined OR=0.63, p=1.90×10⁻⁷). Additional suggestive SNPs were identified near FOXN3, SORCS1 and MMP7/TMEM123 that also confirmed on replication.

Conclusions: Our study suggests a potential role for common genetic variation in several genes that have not previously been implicated in clubfoot pathogenesis.

Keywords: clubfoot; genome wide association study; transcription factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Cell Cycle Proteins / genetics
  • Chromosomes, Human, Pair 12
  • Clubfoot / genetics*
  • Forkhead Transcription Factors
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Humans
  • Matrix Metalloproteinase 7 / genetics
  • Nuclear Receptor Co-Repressor 2 / genetics
  • Polymorphism, Single Nucleotide*
  • Receptors, Cell Surface / genetics
  • Repressor Proteins / genetics
  • White People / genetics


  • Cell Cycle Proteins
  • FOXN3 protein, human
  • Forkhead Transcription Factors
  • NCOR2 protein, human
  • Nuclear Receptor Co-Repressor 2
  • Receptors, Cell Surface
  • Repressor Proteins
  • SORCS1 protein, human
  • MMP7 protein, human
  • Matrix Metalloproteinase 7