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Quantitative traits
Original article
Genome-wide association study identifies new disease loci for isolated clubfoot
  1. Tian-Xiao Zhang1,
  2. Gabe Haller2,
  3. Peng Lin1,
  4. David M Alvarado2,
  5. Jacqueline T Hecht3,
  6. Susan H Blanton4,
  7. B Stephens Richards5,
  8. John P Rice6,
  9. Matthew B Dobbs2,7,
  10. Christina A Gurnett2,8,9
  1. 1Division of Biology and Biomedical Sciences, Washington University School of Medicine, St Louis, Missouri, USA
  2. 2Department of Orthopaedic Surgery, Washington University School of Medicine, St Louis, Missouri, USA
  3. 3Department of Pediatrics, University of Texas Medical School at Houston, Houston, Texas, USA
  4. 4Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, Florida, USA
  5. 5Texas Scottish Rite Hospital for Children, Dallas, Texas, USA
  6. 6Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, USA
  7. 7St Louis Shriners Hospital for Children, St Louis, Missouri, USA
  8. 8Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA
  9. 9Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA
  1. Correspondence to Dr Christina A Gurnett, Department of Neurology, Pediatrics, and Orthopaedic Surgery, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110, USA; gurnettc{at}neuro.wustl.edu

Abstract

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

https://doi.org/10.1136/jmedgenet-2014-102303

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