Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
PLoS One. 2010 Oct 28;5(10):e13712. doi: 10.1371/journal.pone.0013712.
Six independent studies have identified linkage to chromosome 18 for developmental dyslexia or general reading ability. Until now, no candidate genes have been identified to explain this linkage. Here, we set out to identify the gene(s) conferring susceptibility by a two stage strategy of linkage and association analysis.
METHODOLOGY/PRINCIPAL FINDINGS: Linkage analysis: 264 UK families and 155 US families each containing at least one child diagnosed with dyslexia were genotyped with a dense set of microsatellite markers on chromosome 18. Association analysis: Using a discovery sample of 187 UK families, nearly 3000 SNPs were genotyped across the chromosome 18 dyslexia susceptibility candidate region. Following association analysis, the top ranking SNPs were then genotyped in the remaining samples. The linkage analysis revealed a broad signal that spans approximately 40 Mb from 18p11.2 to 18q12.2. Following the association analysis and subsequent replication attempts, we observed consistent association with the same SNPs in three genes; melanocortin 5 receptor (MC5R), dymeclin (DYM) and neural precursor cell expressed, developmentally down-regulated 4-like (NEDD4L).
Along with already published biological evidence, MC5R, DYM and NEDD4L make attractive candidates for dyslexia susceptibility genes. However, further replication and functional studies are still required.
六项独立的研究已经确定了染色体 18 与发育性阅读障碍或一般阅读能力有关。到目前为止，还没有发现可以解释这种联系的候选基因。在这里，我们通过连锁和关联分析的两阶段策略，着手确定易感性的基因。
方法/主要发现：连锁分析：264 个英国家庭和 155 个美国家庭，每个家庭至少有一个被诊断为阅读障碍的孩子，用染色体 18 上的一套密集微卫星标记进行基因分型。关联分析：在一个 187 个英国家庭的发现样本中，在染色体 18 阅读障碍易感候选区域内对近 3000 个 SNP 进行基因分型。关联分析后，然后在其余样本中对排名最高的 SNP 进行基因分型。连锁分析显示出一个广泛的信号，跨越大约 40 Mb，从 18p11.2 到 18q12.2。在关联分析和随后的复制尝试之后，我们观察到在三个基因中的相同 SNP 存在一致的关联；黑皮质素 5 受体 (MC5R)、dymeclin (DYM) 和神经前体细胞表达、发育下调 4 样 (NEDD4L)。
MC5R、DYM 和 NEDD4L 与已经发表的生物学证据一起，成为阅读障碍易感基因的有吸引力的候选基因。然而，仍然需要进一步的复制和功能研究。
