Genome-wide association study identifies multiple susceptibility loci for craniofacial microsomia.
Genome-wide association study identifies multiple susceptibility loci for craniofacial microsomia.
复制标题
全基因组关联研究确定了颅面微小症的多个易感位点。
DOI：
10.1038/ncomms10605
复制
发表时间：
2016-02-08
影响因子：
16.6
通讯作者：
Zhang Q
中科院分区：
文献类型：
--
作者：
Zhang YB;Hu J;Zhang J;Zhou X;Li X;Gu C;Liu T;Xie Y;Liu J;Gu M;Wang P;Wu T;Qian J;Wang Y;Dong X;Yu J;Zhang Q
颅面侏儒症（CFM）是一种罕见的先天性异常，涉及第一和第二咽弓的不成熟衍生物。CFM的遗传发病机制尚不清楚。在这里，我们询问了来自中国的939例CFM病例和2，012例对照中的90万个遗传变异。在对另外443例病例和1,669名对照进行基因分型后，我们确定了8个与最显著SNP rs 13089920显著相关的位点（logistic回归P=2.15 × 10−120）和5个提示性位点。上述13个相关基因座，包括ROBO 1、GATA 3、GBX 2、FGF 3、NRP 2、EDNRB、SHROOM 3、SEMA 7A、PLCD 3、KLF 12和EPAS 1，被发现富集了参与神经嵴细胞（NCC）发育和血管发生的基因。然后，我们对来自病例队列的21个样本进行全基因组测序，并在相关基因座内鉴定出几种新的功能丧失突变。我们的研究结果提供了新的见解颅面矮小症的遗传背景。 颅面矮小症是一种影响颅骨发育的先天性异常。在这里，作者对中国的患者进行了全基因组关联研究，并确定了可为遗传机制提供见解的特定基因座。
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.