Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus
Support for the homeobox transcription factor gene ENGRAILED 2 as an autism spectrum disorder susceptibility locus
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DOI：
10.1086/497705
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发表时间：
2005-11-01
影响因子：
9.8
通讯作者：
Millonig, JH
中科院分区：
文献类型：
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作者：
Benayed, R;Gharani, N;Millonig, JH
我们先前的研究涉及来自自闭症遗传资源交换（AGRE）的167个核心家庭，表明同源结构域转录因子基因ENGRAPHYS 2（EN 2）中的两个内含子SNP rs 1861972和rs 1861973与自闭症谱系障碍（ASD）显著相关。在这项研究中，两个额外的数据集报告了rs 1861972和rs 1861973的显著重复关联：一个独立的222个AGRE家族（rs 1861972-rs 1861973单倍型）和一个单独的129个国家精神卫生研究所家庭（rs 1861972-rs 1861973单倍型）样本。在两个AGRE数据集（389个家庭）的合并样本中，P =.0431单倍型的关联分析产生了.0000033的P值，而合并所有三个数据集（518个家庭）产生了.0000035的P值。使用518个家庭的整个样本进行相关单倍型的人群归因风险计算，确定风险等位基因导致一般人群中多达40%的ASD病例。连锁不平衡（LD）映射与分布在整个基因的多态性的使用表明，只有内含子SNP是在强LD与rs 1861972和rs 1861973。所有内含子SNP的重测序和关联分析已经确定了与ASD相关的等位基因，这使得它们成为未来功能分析的候选者。最后，为了开始定义EN 2在发育过程中的功能，小鼠EN 2在皮质前体中异位表达。与对照相比，较少的En 2转染细胞显示分化的表型。总之，这些数据提供了进一步的遗传证据，EN 2可能作为ASD易感基因座，并且它们表明，干扰EN 2的空间/时间表达的风险等位基因可以显着改变正常的大脑发育。
Our previous research involving 167 nuclear families from the Autism Genetic Resource Exchange (AGRE) demonstrated that two intronic SNPs, rs1861972 and rs1861973, in the homeodomain transcription factor gene ENGRAILED 2 (EN2) are significantly associated with autism spectrum disorder (ASD). In this study, significant replication of association for rs1861972 and rs1861973 is reported for two additional data sets: an independent set of 222 AGRE families (rs1861972-rs1861973 haplotype,) and a separate sample of 129 National P=.0016 Institutes of Mental Health families (rs1861972-rs1861973 haplotype,). Association analysis of the P =.0431 haplotype in the combined sample of both AGRE data sets ( 389 families) produced a P value of .0000033, whereas combining all three data sets ( 518 families) produced a P value of .00000035. Population-attributable risk calculations for the associated haplotype, performed using the entire sample of 518 families, determined that the risk allele contributes to as many as 40% of ASD cases in the general population. Linkage disequilibrium (LD) mapping with the use of polymorphisms distributed throughout the gene has shown that only intronic SNPs are in strong LD with rs1861972 and rs1861973. Resequencing and association analysis of all intronic SNPs have identified alleles associated with ASD, which makes them candidates for future functional analysis. Finally, to begin defining the function of EN2 during development, mouse En2 was ectopically expressed in cortical precursors. Fewer En2 transfected cells than controls displayed a differentiated phenotype. Together, these data provide further genetic evidence that EN2 might act as an ASD susceptibility locus, and they suggest that a risk allele that perturbs the spatial/temporal expression of EN2 could significantly alter normal brain development.