Detecting Gene-Gene Interactions for Cleft Lip with/without Cleft Palate in Targeted Sequencing Data

Orofacial Cleft;gene-gene interaction;Epidemiology

Xiao, YanziBeaty, Terri L. ;

Johns Hopkins University

关键词: Orofacial Cleft;    gene-gene interaction;    Epidemiology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/38046/XIAO-THESIS-2015.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

BackgroundNon-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. All the known genetic risk factors cannot fully explain the observed heritability of NSCL/P, and several authors have suggested gene-gene (GxG) interaction may be important in the etiology of this complex and heterogeneous malformation.ObjectiveWe aimed to detect gene-gene interactions for cleft lip with/without cleft palate in targeted sequencing data. MethodsWe used targeted sequence data on 13 regions identified by previous studies spanning 6.3 MB of the genome in a study of 1,498 case-parent trios. We used R-package Trio to perform a likelihood ratio test (LRT) to test for GxG interaction in both a 1 df test and a 4 df test. To adjust for multiple testing, permutation test was performed to generate empiric p-values. ResultsThe most significant 4df LRT was seen with rs6029315 in MAFB and rs6681255 in IRF6 (p=3.8×10-8) in the European group, which remained significant (p=0.02) after correcting for multiple comparison via permutation tests. Only 2% of replicates generated under the null hypothesis exceeded this observed test statistic. However, we found no pairwise interaction yielding an empirical p<0.05 in the Asian trio group. ConclusionsOur results suggest that there is statistical GxG interaction between IRF6 and MAFB in the European population. Because IRF6 is the only gene that has shown consistency across different types of genetic studies, evidence of statistical interaction between markers in/near the genes IRF6 and MAFB is especially interesting.