Genome-wide Analyses Identify a Novel Risk Locus for Nonsyndromic Cleft Palate
Genome-wide Analyses Identify a Novel Risk Locus for Nonsyndromic Cleft Palate
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全基因组分析确定了非综合征性腭裂的新风险位点
DOI：
10.1177/0022034520943867
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发表时间：
2020-08-06
影响因子：
7.6
通讯作者：
Bian, Z.
中科院分区：
文献类型：
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作者：
He, M.;Zuo, X.;Bian, Z.
在非综合征性口面裂（NSOFCs）患者中观察到的3种主要亚表型为非综合征性单纯唇裂（NSCLO）、非综合征性唇腭裂（NSCLP）和非综合征性单纯腭裂（NSCPO）。然而，NSCPO的遗传结构基本上是未知的。在这里，我们进行了一个2阶段的全基因组关联研究（GWAS）的NSCPO和复制分析的其他NSOFCs从中国汉族人群中选择的变异。我们确定了一个新的基因座（15q24.3）和一个已知的基因座（1q32.2），在病例对照设计中，在与NSCPO相关的检验中，该基因内或附近的变异达到了全基因组显著性（2.80 × 10−13 < P < 1.72 × 10−08）。虽然发现15q24.3的变异与NSCPO和NSCLP显著相关，但估计对风险的影响方向相反。我们对15q24.3内风险等位基因的功能注释，加上先前确定的候选基因在围产期发育、胚胎发育和/或细胞过程调节中的风险基因座内的作用，支持它们参与腭裂发育和腭裂发病机制。我们的研究推进了对NSOFCs遗传基础的理解，并为NSCPO的发病机制提供了新的见解。
The 3 major subphenotypes observed in patients with nonsyndromic orofacial clefts (NSOFCs) are nonsyndromic cleft lip only (NSCLO), nonsyndromic cleft lip with palate (NSCLP), and nonsyndromic cleft palate only (NSCPO). However, the genetic architecture underlying NSCPO is largely unknown. Here we performed a 2-stage genome-wide association study (GWAS) on NSCPO and replication analyses of selected variants in other NSOFCs from the Chinese Han population. We identified a novel locus (15q24.3) and a known locus (1q32.2) where variants in or near the gene reached genome-wide significance (2.80 × 10−13 < P < 1.72 × 10−08) in a test for association with NSCPO in a case-control design. Although a variant from 15q24.3 was found to be significantly associated with both NSCPO and NSCLP, the direction of estimated effects on risk were opposite. Our functional annotation of the risk alleles within 15q24.3 coupled with previously established roles of the candidate genes within identified risk loci in periderm development, embryonic patterning, and/or regulation of cellular processes supports their involvement in palate development and the pathogenesis of cleft palate. Our study advances the understanding of the genetic basis of NSOFCs and provides novel insights into the pathogenesis of NSCPO.