Francks Clyde, Paracchini Silvia, Smith Shelley D, Richardson Alex J, Scerri Tom S, Cardon Lon R, Marlow Angela J, MacPhie I Laurence, Walter Janet, Pennington Bruce F, Fisher Simon E, Olson Richard K, DeFries John C, Stein John F, Monaco Anthony P
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Am J Hum Genet. 2004 Dec;75(6):1046-58. doi: 10.1086/426404. Epub 2004 Oct 22.
Several quantitative trait loci (QTLs) that influence developmental dyslexia (reading disability [RD]) have been mapped to chromosome regions by linkage analysis. The most consistently replicated area of linkage is on chromosome 6p23-21.3. We used association analysis in 223 siblings from the United Kingdom to identify an underlying QTL on 6p22.2. Our association study implicates a 77-kb region spanning the gene TTRAP and the first four exons of the neighboring uncharacterized gene KIAA0319. The region of association is also directly upstream of a third gene, THEM2. We found evidence of these associations in a second sample of siblings from the United Kingdom, as well as in an independent sample of twin-based sibships from Colorado. One main RD risk haplotype that has a frequency of approximately 12% was found in both the U.K. and U.S. samples. The haplotype is not distinguished by any protein-coding polymorphisms, and, therefore, the functional variation may relate to gene expression. The QTL influences a broad range of reading-related cognitive abilities but has no significant impact on general cognitive performance in these samples. In addition, the QTL effect may be largely limited to the severe range of reading disability.
通过连锁分析，已将几个影响发育性阅读障碍（诵读困难[RD]）的数量性状基因座（QTL）定位到染色体区域。最一致重复的连锁区域位于6号染色体的6p23 - 21.3。我们对来自英国的223对同胞进行了关联分析，以确定6p22.2上的潜在QTL。我们的关联研究表明，一个77 kb的区域涵盖了TTRAP基因以及相邻未表征基因KIAA0319的前四个外显子。关联区域也位于第三个基因THEM2的直接上游。我们在来自英国的另一组同胞样本以及来自科罗拉多州的基于双胞胎的同胞独立样本中发现了这些关联的证据。在英国和美国样本中均发现了一种主要的RD风险单倍型，其频率约为12%。该单倍型没有任何蛋白质编码多态性特征，因此，功能变异可能与基因表达有关。该QTL影响广泛的阅读相关认知能力，但对这些样本中的一般认知表现没有显著影响。此外，QTL效应可能在很大程度上仅限于严重程度的阅读障碍。
