Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft

• Published in: PLoS genetics Vol. 15; no. 10; p. e1008357
• Main Authors: Huang, Lulin, Jia, Zhonglin, Shi, Yi, Du, Qin, Shi, Jiayu, Wang, Ziyan, Mou, Yandong, Wang, Qingwei, Zhang, Bihe, Wang, Qing, Ma, Shi, Lin, He, Duan, Shijun, Yin, Bin, Lin, Yansong, Wang, Yiru, Jiang, Dan, Hao, Fang, Zhang, Lin, Wang, Haixin, Jiang, Suyuan, Xu, Huijuan, Yang, Chengwei, Li, Chenghao, Li, Jingtao, Shi, Bing, Yang, Zhenglin
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14.10.2019; Public Library of Science (PLoS)
• Subjects: Alleles; Analysis; Biology; Biology and Life Sciences; Birth defects; Brain - abnormalities; Brain - physiopathology; Cleft lip; Cleft Lip - genetics; Cleft Lip - physiopathology; Cleft lip/palate; Cleft palate; Cleft Palate - genetics; Cleft Palate - physiopathology; Collateralized loan obligations; Congenital defects; Criminal investigation; DNA binding proteins; Embryogenesis; Embryonic development; Factor analysis; Gene dosage; Gene Dosage - genetics; Gene expression; Gene Expression Regulation - genetics; Gene Regulatory Networks - genetics; Genes; Genetic analysis; Genetic diversity; Genetic factors; Genetic polymorphisms; Genetic Predisposition to Disease; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Genotype; Hospitals; Humans; Interferon Regulatory Factors - genetics; Medical laboratories; Medicine; Medicine and Health Sciences; Methods; Novels; Oral diseases; Otolaryngology; PAX9 Transcription Factor - genetics; People and places; Polymorphism, Single Nucleotide - genetics; Product development; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Software; Transcription factors; Veterinarians; China
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1008357

Nonsyndromic orofacial cleft (NSOFC) is a severe birth defect that occurs early in embryonic development and includes the subtypes cleft palate only (CPO), cleft lip only (CLO) and cleft lip with cleft palate (CLP). Given a lack of specific genetic factor analysis for CPO and CLO, the present study aimed to dissect the landscape of genetic factors underlying the pathogenesis of these two subtypes using 6,986 cases and 10,165 controls. By combining a genome-wide association study (GWAS) for specific subtypes of CPO and CLO, as well as functional gene network and ontology pathway analysis, we identified 18 genes/loci that surpassed genome-wide significance (P < 5 × 10-8) responsible for NSOFC, including nine for CPO, seven for CLO, two for both conditions and four that contribute to the CLP subtype. Among these 18 genes/loci, 14 are novel and identified in this study and 12 contain developmental transcription factors (TFs), suggesting that TFs are the key factors for the pathogenesis of NSOFC subtypes. Interestingly, we observed an opposite effect of the genetic variants in the IRF6 gene for CPO and CLO. Moreover, the gene expression dosage effect of IRF6 with two different alleles at the same single-nucleotide polymorphism (SNP) plays important roles in driving CPO or CLO. In addition, PAX9 is a key TF for CPO. Our findings define subtypes of NSOFC using genetic factors and their functional ontologies and provide a clue to improve their diagnosis and treatment in the future.