Harold D, Paracchini S, Scerri T, Dennis M, Cope N, Hill G, Moskvina V, Walter J, Richardson A J, Owen M J, Stein J F, Green E D, O'Donovan M C, Williams J, Monaco A P
Department of Psychological Medicine, Cardiff University, Heath Park, Cardiff, UK.
Mol Psychiatry. 2006 Dec;11(12):1085-91, 1061. doi: 10.1038/sj.mp.4001904. Epub 2006 Oct 10.
The DYX2 locus on chromosome 6p22.2 is the most replicated region of linkage to developmental dyslexia (DD). Two candidate genes within this region have recently been implicated in the disorder: KIAA0319 and DCDC2. Variants within DCDC2 have shown association with DD in a US and a German sample. However, when we genotyped these specific variants in two large, independent UK samples, we obtained only weak, inconsistent evidence for their involvement in DD. Having previously found evidence that variation in the KIAA0319 gene confers susceptibility to DD, we sought to refine this genetic association by genotyping 36 additional SNPs in the gene. Nine SNPs, predominantly clustered around the first exon, showed the most significant association with DD in one or both UK samples, including rs3212236 in the 5' flanking region (P = 0.00003) and rs761100 in intron 1 (P = 0.0004). We have thus refined the region of association with developmental dyslexia to putative regulatory sequences around the first exon of the KIAA0319 gene, supporting the presence of functional mutations that could affect gene expression. Our data also suggests a possible interaction between KIAA0319 and DCDC2, which requires further testing.
位于6号染色体p22.2区域的DYX2位点是与发育性阅读障碍（DD）连锁关系中最易重复出现的区域。该区域内的两个候选基因最近被认为与这种疾病有关：KIAA0319和DCDC2。在一个美国样本和一个德国样本中，DCDC2基因内的变异已显示出与DD存在关联。然而，当我们在两个大型、独立的英国样本中对这些特定变异进行基因分型时，仅获得了关于它们与DD相关的微弱、不一致的证据。我们之前已发现证据表明KIAA0319基因的变异会使人易患DD，因此我们试图通过对该基因另外36个单核苷酸多态性（SNP）进行基因分型来完善这种遗传关联。九个SNP，主要集中在第一个外显子周围，在一个或两个英国样本中显示出与DD最显著的关联，包括5'侧翼区域的rs3212236（P = 0.00003）和内含子1中的rs761100（P = 0.0004）。因此，我们已将与发育性阅读障碍相关的区域细化到KIAA0319基因第一个外显子周围的假定调控序列，这支持了可能存在影响基因表达的功能性突变。我们的数据还表明KIAA0319和DCDC2之间可能存在相互作用，这需要进一步验证。
