title: Gene-gene interaction of single nucleotide polymorphisms in 16p13.3 may contribute to the risk of non-syndromic cleft lip with or without cleft palate in Chinese case-parent trios.
abstract: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with a complex and heterogeneous etiology. A recent genome-wide association study (GWAS) among Chinese populations has identified a new region at 16p13.3 as being associated with NSCL/P, which requires further replication. Here, we attempted to replicate and further clarify the genetic association between this region and NSCL/P, as well as testing for potential gene-gene (G × G) and gene-environment (G × E) interactions. We conducted transmission disequilibrium tests on 69 single nucleotide polymorphisms (SNPs) mapping to 16p13.3 among 806 Chinese case-parent trios ascertained through an international consortium where a GWAS of oral clefts was conducted. G × G, as well as G × E interactions involving maternal environmental tobacco smoke (ETS) and multivitamin supplementation, were explored using conditional logistic regression model. We applied Cordell's method as implemented in the R package TRIO to test for possible interactions. While no SNPs showed evidence of linkage and association with NSCL/P after Bonferroni correction, we found signals of G × G interactions between SNPs in 16p13.3. Nine pairs of SNP-SNP interactions attained significance after Bonferroni correction, among which the most significant interaction was found between rs2072346 (ADCY9) and rs11646137 (intergenic region, P = 7.2 × 10-5). Linkage disequilibrium (LD) analysis revealed only low level of LD between these SNPs. This study failed to confirm the significant association between SNPs within 16p13.3 and the risk of NSCL/P, but underlined the importance of taking into account potential G × G interactions for the genetic association analysis of NSCL/P.
authors.affiliation: School of Public Health, Peking University, Beijing, China.
authors.forename: Dongjing
authors.identifier: http://orcid.org/0000-0002-9520-7789
authors.initials: D
authors.lastname: Liu
authors.affiliation: School of Public Health, Peking University, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Mathematical Institute, Heinrich Heine University Duesseldorf, Duesseldorf, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Schwender
authors.affiliation: Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
authors.affiliation: School of Public Health, Peking University, Beijing, China.
authors.forename: Zhuqing
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Public Health, Peking University, Beijing, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Beijing Center for Disease Prevention and Control, Beijing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: National Yang-Ming University, Taipei, Taiwan.
authors.forename: Kung Yee
authors.initials: KY
authors.lastname: Liang
authors.affiliation: Chang Gung Memorial Hospital, Taoyuan, Taiwan.
authors.forename: Yah Huei
authors.initials: YH
authors.lastname: Wu-Chou
authors.affiliation: School of Public Health, Peking University, Beijing, China.
authors.forename: Mengying
authors.initials: M
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Oral Disease, West China College of Stomatology, Sichuan University, Chengdu, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Shi
authors.affiliation: School of Stomatology, Peking University, Beijing, China.
authors.forename: Hongping
authors.initials: H
authors.lastname: Zhu
authors.affiliation: School of Public Health, Peking University, Beijing, China.|Key Laboratory of Reproductive Health, Ministry of Health, Beijing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.affiliation: School of Public Health, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
mesh_terms: D001921:Brain / Q000002:abnormalities* / Q000503:physiopathology; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D002971:Cleft Lip / Q000235:genetics* / Q000503:physiopathology; D002972:Cleft Palate / Q000235:genetics* / Q000503:physiopathology; D004843:Epistasis, Genetic / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
keywords: case-parent trios; gene-gene interaction; genome-wide association study; non-syndromic cleft lip with or without cleft palate