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Genet Epidemiol. 2017 Apr;41(3):244-250. doi: 10.1002/gepi.22023. Epub 2016 Dec 26.

Evidence for SNP-SNP interaction identified through targeted sequencing of cleft case-parent trios.

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Department of Epidemiology, School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Mathematical Institute, Heinrich Heine University, Düsseldorf, Germany.
Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
The Genome Institute, Washington University School of Medicine, St. Louis, MO, USA.
Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.


Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is the most common craniofacial birth defect in humans, affecting 1 in 700 live births. This malformation has a complex etiology where multiple genes and several environmental factors influence risk. At least a dozen different genes have been confirmed to be associated with risk of NSCL/P in previous studies. However, all the known genetic risk factors cannot fully explain the observed heritability of NSCL/P, and several authors have suggested gene-gene (G × G) interaction may be important in the etiology of this complex and heterogeneous malformation. We tested for G × G interactions using common single nucleotide polymorphic (SNP) markers from targeted sequencing in 13 regions identified by previous studies spanning 6.3 Mb of the genome in a study of 1,498 NSCL/P case-parent trios. We used the R-package trio to assess interactions between polymorphic markers in different genes, using a 1 degree of freedom (1df) test for screening, and a 4 degree of freedom (4df) test to assess statistical significance of epistatic interactions. To adjust for multiple comparisons, we performed permutation tests. The most significant interaction was observed between rs6029315 in MAFB and rs6681355 in IRF6 (4df P = 3.8 × 10-8 ) in case-parent trios of European ancestry, which remained significant after correcting for multiple comparisons. However, no significant interaction was detected in trios of Asian ancestry.


case-parent trios; gene-gene interaction; oral clefts

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