Genome-wide association study identifies new disease loci for isolated clubfoot.
Genome-wide association study identifies new disease loci for isolated clubfoot.
复制标题
全基因组关联研究确定了孤立性马蹄内翻足的新疾病位点。
DOI：
10.1136/jmedgenet-2014-102303
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发表时间：
2014
影响因子：
4
通讯作者：
Gurnett,ChristinaA
中科院分区：
文献类型：
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作者：
Zhang,Tian-Xiao;Haller,Gabe;Lin,Peng;Alvarado,DavidM;Hecht,JacquelineT;Blanton,SusanH;StephensRichards,B;Rice,JohnP;Dobbs,MatthewB;Gurnett,ChristinaA
研究背景马蹄内翻足是一种常见的先天性出生缺陷，具有复杂的遗传模式。目前，人们对马蹄足的遗传和形态学基础知之甚少。为了确定与马蹄内翻足相关的遗传风险因素，我们对常见遗传变异进行了全基因组关联研究。方法使用 Affymetrix 6.0 芯片对 396 名马蹄内翻足患者和 1000 名欧洲血统对照者的 DNA 进行了 >600 000 个单核苷酸多态性 (SNP) 的基因分型。对 370 例孤立的马蹄足病例和 363 名欧洲血统对照的独立队列进行复制。结果发现马蹄内翻足关联的最有力证据是染色体 12q24.31 上 NCOR2 和 ZNF664 之间的基因间 SNP（rs7969148，OR=0.58，p=1.25×10−5），该 SNP 对复制具有显着性（组合 OR=0.63， p=1.90×10−7)。在 FOXN3、SORCS1 和 MMP7/TMEM123 附近发现了其他提示性 SNP，这些 SNP 也在复制中得到证实。结论我们的研究表明，先前未涉及马蹄内翻足发病机制的几个基因中常见遗传变异的潜在作用。
BackgroundClubfoot is a common congenital birth defect with complex inheritance patterns. Currently, the genetic and morphological basis of clubfoot is poorly understood. To identify genetic risk factors associated with clubfoot, we performed a genome-wide association study of common genetic variants.MethodsThe DNA of 396 isolated clubfoot patients and 1000 controls of European descent was genotyped for >600 000 single nucleotide polymorphisms (SNP) using the Affymetrix 6.0 array. Replication was performed with an independent cohort of 370 isolated clubfoot cases and 363 controls of European descent.ResultsStrongest evidence for an association of clubfoot was found with an intergenic SNP on chromosome 12q24.31 betweenNCOR2andZNF664(rs7969148, OR=0.58, p=1.25×10−5) that was significant on replication (combined OR=0.63, p=1.90×10−7). Additional suggestive SNPs were identified nearFOXN3,SORCS1andMMP7/TMEM123that also confirmed on replication.ConclusionsOur study suggests a potential role for common genetic variation in several genes that have not previously been implicated in clubfoot pathogenesis.