Genetic factors define CPO and CLO subtypes of nonsyndromicorofacial cleft

English version

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: https://doi.org/10.1371/journal.pgen.1008357

Souhrn

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

Zdroje

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