Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft

Autoři: Lulin Huang aff001;  Zhonglin Jia aff002;  Yi Shi aff001;  Qin Du aff001;  Jiayu Shi aff005;  Ziyan Wang aff006;  Yandong Mou aff004;  Qingwei Wang aff001;  Bihe Zhang aff002;  Qing Wang aff002;  Shi Ma aff001;  He Lin aff001;  Shijun Duan aff002;  Bin Yin aff002;  Yansong Lin aff002;  Yiru Wang aff002;  Dan Jiang aff001;  Fang Hao aff001;  Lin Zhang aff001;  Haixin Wang aff001;  Suyuan Jiang aff002;  Huijuan Xu aff003;  Chengwei Yang aff002;  Chenghao Li aff002;  Jingtao Li aff002;  Bing Shi aff002;  Zhenglin Yang aff001
Působiště autorů: The Sichuan Provincial Key Laboratory for Human Disease Gene Study, Department of Clinical Laboratory, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China aff001;  State Key Laboratory of Oral Diseases and National Clinical Research Center for Oral Diseases and Department of cleft lip and palate, West China Hospital of Stomatology, Sichuan University, Chengdu, China aff002;  Institute of Chengdu Biology, and Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China aff003;  Department of Stomatology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China aff004;  Division of Growth and Development and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, United States of America aff005;  Department of basic medicine, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China aff006
Vyšlo v časopise: Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft. PLoS Genet 15(10): e32767. doi:10.1371/journal.pgen.1008357
Kategorie: Research Article
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.

Klíčová slova:

Gene expression – Gene ontologies – Genetic loci – Genome-wide association studies – Han Chinese people – Cleft lip – Cleft lip and palate – Cleft palate


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