Genetic determinants of facial clefting: analysis of 357 candidate genes using two national cleft studies from Scandinavia.
Genetic determinants of facial clefting: analysis of 357 candidate genes using two national cleft studies from Scandinavia.
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DOI：
10.1371/journal.pone.0005385
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发表时间：
2009
期刊：
影响因子：
3.7
通讯作者：
Murray JC
中科院分区：
文献类型：
--
作者：
Jugessur A;Shi M;Gjessing HK;Lie RT;Wilcox AJ;Weinberg CR;Christensen K;Boyles AL;Daack-Hirsch S;Trung TN;Bille C;Lidral AC;Murray JC
面部裂是一种常见的先天缺陷，具有很强的遗传成分。为了确定胎儿裂的遗传风险因素，在来自斯堪的纳维亚的两个基于人群的样本中对357个候选基因中的1536个SNP进行基因分型（挪威：562个病例-父母和592个对照-父母三联体;丹麦：235个病例-父母三联体）。我们使用了两种互补的统计方法，TRIMM和HAPLIN，来寻找这两个国家样本之间的关联。TRIMM通过直接使用来自病例-亲本三联体的多SNP基因型来测试每个基因中的关联，而不需要推断单倍型。另一方面，HAPLIN估计一组SNP的完整单倍型分布，并估计与每个单倍型相关的相对风险。对于孤立性唇裂伴或不伴腭裂（I-CL/P），TRIMM和HAPLIN均在两个人群中发现与IRF 6和ADH 1C显著相关，但只有HAPLIN发现与FGF 12相关。对于孤立性腭裂（I-CP），TRIMM发现与ALX 3，MKX和PDGFC在两个人群中的关联，但只有与PDGFC的关联被HAPLIN确定。此外，HAPLIN还发现了TRIMM未检测到的与ETV 5的相关性。在斯堪的纳维亚样本中复制了与七个基因的强关联，我们的方法有效地复制了先前已知的与IRF 6的最强关联。基于两个具有相似祖先的国家裂缝队列，两种强大的统计方法和迄今为止最有希望的裂缝候选基因中的一大组SNP，这项研究确定了以前未知的与ADH 1C裂缝的关联，并提供了额外的候选人和分析方法来推进该领域。
Facial clefts are common birth defects with a strong genetic component. To identify fetal genetic risk factors for clefting, 1536 SNPs in 357 candidate genes were genotyped in two population-based samples from Scandinavia (Norway: 562 case-parent and 592 control-parent triads; Denmark: 235 case-parent triads). We used two complementary statistical methods, TRIMM and HAPLIN, to look for associations across these two national samples. TRIMM tests for association in each gene by using multi-SNP genotypes from case-parent triads directly without the need to infer haplotypes. HAPLIN on the other hand estimates the full haplotype distribution over a set of SNPs and estimates relative risks associated with each haplotype. For isolated cleft lip with or without cleft palate (I-CL/P), TRIMM and HAPLIN both identified significant associations with IRF6 and ADH1C in both populations, but only HAPLIN found an association with FGF12. For isolated cleft palate (I-CP), TRIMM found associations with ALX3, MKX, and PDGFC in both populations, but only the association with PDGFC was identified by HAPLIN. In addition, HAPLIN identified an association with ETV5 that was not detected by TRIMM. Strong associations with seven genes were replicated in the Scandinavian samples and our approach effectively replicated the strongest previously known association in clefting—with IRF6. Based on two national cleft cohorts of similar ancestry, two robust statistical methods and a large panel of SNPs in the most promising cleft candidate genes to date, this study identified a previously unknown association with clefting for ADH1C and provides additional candidates and analytic approaches to advance the field.
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