Cope Natalie, Harold Denise, Hill Gary, Moskvina Valentina, Stevenson Jim, Holmans Peter, Owen Michael J, O'Donovan Michael C, Williams Julie
Department of Psychological Medicine, Wales College of Medicine, Cardiff University, Cardiff, United Kingdom.
Am J Hum Genet. 2005 Apr;76(4):581-91. doi: 10.1086/429131. Epub 2005 Feb 16.
Linkage between developmental dyslexia (DD) and chromosome 6p has been replicated in a number of independent samples. Recent attempts to identify the gene responsible for the linkage have produced inconsistent evidence for association of DD with a number of genes in a 575-kb region of chromosome 6p22.2, including VMP, DCDC2, KIAA0319, TTRAP, and THEM2. We aimed to identify the specific gene or genes involved by performing a systematic, high-density (approximately 2-3-kb intervals) linkage disequilibrium screen of these genes in an independent sample, incorporating family-based and case-control designs in which dyslexia was defined as an extreme representation of reading disability. Using DNA pooling, we first observed evidence for association with 17 single-nucleotide polymorphisms (SNPs), 13 of which were located in the KIAA0319 gene (P<.01-.003). After redundant SNPs were excluded, 10 SNPs were individually genotyped in 223 subjects with DD and 273 controls. Those SNPs that were significant at P</=.05 were next genotyped in a semi-independent sample of 143 trios of probands with DD and their parents, to control for possible population stratification. Six SNPs showed significant evidence of association in both samples (P</=.04-.002), including a SNP (rs4504469) in exon 4 of the KIAA0319 gene that changes an amino acid (P=.002; odds ratio 1.5). Logistic regression analysis showed that two SNPs (rs4504469 and rs6935076) in the KIAA0319 gene best explained DD status. The haplotype composed of these two markers was significantly associated with DD (global P=.00001 in the case-control sample; P=.02 in trios). This finding was largely driven by underrepresentation of the most common haplotype in cases (P=.00003 in the case-control sample; P=.006 in trios; 1-degree-of-freedom tests). Our data strongly implicate KIAA0319 as a susceptibility gene for dyslexia. The gene product is expressed in brain, but its specific function is currently unknown.
发育性阅读障碍（DD）与6号染色体之间的连锁关系已在多个独立样本中得到验证。最近，人们试图确定导致这种连锁关系的基因，但对于DD与6号染色体短臂2区2带（6p22.2）一个575kb区域内的多个基因（包括VMP、DCDC2、KIAA0319、TTRAP和THEM2）之间的关联，所得到的证据并不一致。我们的目标是通过在一个独立样本中对这些基因进行系统的、高密度（间隔约2 - 3kb）的连锁不平衡筛查来确定具体涉及的一个或多个基因，采用基于家系和病例对照的设计，其中阅读障碍被定义为阅读能力缺陷的极端表现。使用DNA池，我们首先观察到与17个单核苷酸多态性（SNP）存在关联的证据，其中13个位于KIAA0319基因中（P <.01 -.003）。在排除冗余SNP后，对223名DD患者和27名对照个体进行了10个SNP的个体基因分型。接下来，在一个由143名DD先证者及其父母组成的半独立三联体样本中对P≤.05时具有显著性的那些SNP进行基因分型，以控制可能的群体分层。六个SNP在两个样本中均显示出显著的关联证据（P≤.04 -.002），包括KIAA0319基因第4外显子中的一个SNP（rs4504469），该SNP会导致一个氨基酸发生改变（P =.002；优势比为1.5）。逻辑回归分析表明，KIAA0319基因中的两个SNP（rs4504469和rs6935076）能最好地解释DD状态。由这两个标记组成的单倍型与DD显著相关（在病例对照样本中全局P =.00001；在三联体样本中P =.02）。这一发现主要是由于病例中最常见单倍型的比例过低所致（在病例对照样本中P =.00003；在三联体样本中P =.006；自由度为1的检验）。我们的数据有力地表明KIAA0319是阅读障碍的一个易感基因。该基因产物在大脑中表达，但其具体功能目前尚不清楚。
