Association studies of low-frequency coding variants in nonsyndromic cleft lip with or without cleft palate

Research output: Contribution to journalJournal article


  • Elizabeth J Leslie
  • Jenna C Carlson
  • John R Shaffer
  • Carmen J Buxó
  • Eduardo E. Castilla
  • Kaare Christensen
  • Frederic W-B Deleyiannis
  • L Leigh Field
  • Jacqueline T Hecht
  • Lina Moreno
  • Ieda M. Orioli
  • Carmencita D Padilla
  • Alexandre R. Vieira
  • George L Wehby
  • Eleanor Feingold
  • Seth M Weinberg
  • Jeffrey C Murray
  • Mary L Marazita

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Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a group of common human birth defects with complex etiology. Although genome-wide association studies have successfully identified a number of risk loci, these loci only account for about 20% of the heritability of orofacial clefts. The "missing" heritability may be found in rare variants, copy number variants, or interactions. In this study, we investigated the role of low-frequency variants genotyped in 1995 cases and 1626 controls on the Illumina HumanCore + Exome chip. We performed two statistical tests, Sequence Kernel Association Test (SKAT) and Combined Multivariate and Collapsing (CMC) method using two minor allele frequency cutoffs (1% and 5%). We found that a burden of low-frequency coding variants in N4BP2, CDSN, PRTG, and AHRR were associated with increased risk of NSCL/P. Low-frequency variants in other genes were associated with decreased risk of NSCL/P. These results demonstrate that low-frequency variants contribute to the genetic etiology of NSCL/P.

JournalAmerican Journal of Medical Genetics. Part A
Issue number6
Pages (from-to)1531-1538
StatePublished - 2017

    Research areas

  • Journal Article