Xiao Yanzi, Taub Margaret A, Ruczinski Ingo, Begum Ferdouse, Hetmanski Jacqueline B, Schwender Holger, Leslie Elizabeth J, Koboldt Daniel C, Murray Jeffrey C, Marazita Mary L, Beaty Terri H
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.
Genet Epidemiol. 2017 Apr;41(3):244-250. doi: 10.1002/gepi.22023. Epub 2016 Dec 26.
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 ) 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.
非综合征性唇裂伴或不伴腭裂（NSCL/P）是人类最常见的颅面出生缺陷，每700例活产中就有1例受影响。这种畸形具有复杂的病因，多种基因和若干环境因素会影响患病风险。在先前的研究中，至少有十二种不同的基因已被证实与NSCL/P的风险相关。然而，所有已知的遗传风险因素都无法完全解释观察到的NSCL/P遗传力，一些作者认为基因-基因（G×G）相互作用可能在这种复杂且异质性畸形的病因中起重要作用。在一项对1498个NSCL/P病例-父母三联体的研究中，我们使用来自靶向测序的常见单核苷酸多态性（SNP）标记，在先前研究确定的13个区域中测试了G×G相互作用，这些区域跨越基因组的6.3 Mb。我们使用R包trio来评估不同基因中多态性标记之间的相互作用，使用1自由度（1df）检验进行筛选，并使用4自由度（4df）检验来评估上位性相互作用的统计显著性。为了校正多重比较，我们进行了置换检验。在欧洲血统的病例-父母三联体中，观察到MAFB中的rs6029315与IRF6中的rs6681355之间存在最显著的相互作用（4df P = 3.8×10），在校正多重比较后仍然显著。然而，在亚洲血统的三联体中未检测到显著的相互作用。
