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

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          Abstract

          Non-syndromic 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 SNPs derived 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.

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          Author and article information

          Journal
          8411723
          3864
          Genet Epidemiol
          Genet. Epidemiol.
          Genetic epidemiology
          0741-0395
          1098-2272
          27 October 2016
          26 December 2016
          April 2017
          01 April 2018
          : 41
          : 3
          : 244-250
          Affiliations
          [1 ]Department of Epidemiology, School of Public Health, Johns Hopkins University, Baltimore MD, USA 21205
          [2 ]Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore MD, USA 21205
          [3 ]Mathematical Institute, Heinrich Heine University, Düsseldorf, Germany
          [4 ]Center for Craniofacial and Dental Genetics, Department of Oral Biology, School of Dental Medicine, University of Pittsburgh, Pittsburgh, PA, USA
          [5 ]The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA
          [6 ]Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA
          Article
          PMC5340569 PMC5340569 5340569 nihpa825456
          10.1002/gepi.22023
          5340569
          28019042
          a759109c-eda4-49f6-923e-7d047ffdbbd3
          History
          Categories
          Article

          Oral clefts,gene-gene interaction,case-parent trios
          Oral clefts, gene-gene interaction, case-parent trios

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