Genome-wide association study identifies multiple susceptibility loci for craniofacial microsomia

• Published in: Nature communications 2016-02, Vol.7 (1), p.10605-10605, Article 10605
• Main Authors: Zhang, Yong-Biao, Hu, Jintian, Zhang, Jiao, Zhou, Xu, Li, Xin, Gu, Chaohao, Liu, Tun, Xie, Yangchun, Liu, Jiqiang, Gu, Mingliang, Wang, Panpan, Wu, Tingting, Qian, Jin, Wang, Yue, Dong, Xiaoqun, Yu, Jun, Zhang, Qingguo
• Format: Article
• Language: English
• Subjects: 631/208/205/2138; 631/208/2489/144; 631/208/457; 692/699/1670/1669; Adolescent; Adult; Animals; Antigens, CD - genetics; Asian People - genetics; Basic Helix-Loop-Helix Transcription Factors - genetics; Chick Embryo; Child; Child, Preschool; China; Female; Fibroblast Growth Factor 3 - genetics; GATA3 Transcription Factor - genetics; Gene Expression Regulation, Developmental; Genetic Predisposition to Disease; Genome-Wide Association Study; Goldenhar Syndrome - genetics; GPI-Linked Proteins - genetics; Homeodomain Proteins - genetics; Humanities and Social Sciences; Humans; In Situ Hybridization; Kruppel-Like Transcription Factors - genetics; Logistic Models; Male; Mice; Microfilament Proteins - genetics; Middle Aged; multidisciplinary; Neovascularization, Physiologic - genetics; Nerve Tissue Proteins - genetics; Neural Crest - embryology; Neuropilin-2 - genetics; Phospholipase C delta - genetics; Polymorphism, Single Nucleotide; Receptor, Endothelin B - genetics; Receptors, Immunologic - genetics; Roundabout Proteins; Science; Science (multidisciplinary); Semaphorins - genetics; Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms10605

Craniofacial microsomia (CFM) is a rare congenital anomaly that involves immature derivatives from the first and second pharyngeal arches. The genetic pathogenesis of CFM is still unclear. Here we interrogate 0.9 million genetic variants in 939 CFM cases and 2,012 controls from China. After genotyping of an additional 443 cases and 1,669 controls, we identify 8 significantly associated loci with the most significant SNP rs13089920 (logistic regression P =2.15 × 10 −120 ) and 5 suggestive loci. The above 13 associated loci, harboured by candidates of ROBO1 , GATA3 , GBX2 , FGF3 , NRP2 , EDNRB , SHROOM3 , SEMA7A , PLCD3 , KLF12 and EPAS1 , are found to be enriched for genes involved in neural crest cell (NCC) development and vasculogenesis. We then perform whole-genome sequencing on 21 samples from the case cohort, and identify several novel loss-of-function mutations within the associated loci. Our results provide new insights into genetic background of craniofacial microsomia. Craniofacial microsomia is a congenital anomaly that affects the development of the skull. Here, the authors perform a genome-wide association study on patients in China and identify particular loci that provide insights into genetic mechanisms.