Chapman Nicola H, Navas Patrick A, Dorschner Michael O, Mehaffey Michele, Wigg Karen G, Price Kaitlyn M, Naumova Oxana Y, Kerr Elizabeth N, Guger Sharon L, Lovett Maureen W, Grigorenko Elena L, Berninger Virginia, Barr Cathy L, Wijsman Ellen M, Raskind Wendy H
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
Department of Pediatrics, Division of Pediatric Genetics, Pediatric Genetics, University of Washington, Seattle, Washington, United States of America.
PLoS One. 2025 May 27;20(5):e0324006. doi: 10.1371/journal.pone.0324006. eCollection 2025.
Dyslexia is a common learning impairment with a genetic basis that affects word reading and spelling. An increasing list of loci and genes have been implicated, but analyses to-date have investigated only limited genomic variation within each locus with no confirmed pathogenic variants identified. Our study is the first to comprehensively sequence both coding and cis-acting regulatory regions of such genes in a large study sample. In a collection of >2000 participants in families from three independent sites, we performed targeted capture and comprehensive sequencing of all exons and some regulatory elements of five candidate risk genes (DNAAF4, CYP19A1, DCDC2, KIAA0319 and GRIN2B) for which prior evidence for a role in dyslexia exists from more than one sample. We evaluated evidence for association in each of six dyslexia-related quantitative phenotypes (traits) using both individual common single nucleotide polymorphisms and aggregated rare variants. We detected no promoter alterations and few deleterious variants in the coding exons, none of which showed evidence of association with any trait. Single variant and aggregate testing of DNAAF4 failed to detect significant evidence of association with any of the traits. The other four genes provided evidence of association with one or more traits. A common variant downstream of CYP19A1 showed significant evidence of association with multiple traits with or without verbal IQ (VIQ) adjustment. A haplotype that stretches from the downstream region of KIAA0319 to the second intron of DCDC2 was associated with reduced performance on timed real word reading. Finally, rare exonic variants in GRIN2B were associated with performance on spelling, with or without adjustment for VIQ. Our findings from this large-scale sequencing study complement those from genome-wide association studies, argue against the causative involvement of large-effect coding variants in these five candidate genes, support a multigenic etiology, and suggest a role of transcriptional regulation.
阅读障碍是一种常见的具有遗传基础的学习障碍，会影响单词阅读和拼写。越来越多的基因座和基因被牵涉其中，但迄今为止的分析仅研究了每个基因座内有限的基因组变异，尚未鉴定出已确认的致病变异。我们的研究首次在一个大型研究样本中对这类基因的编码区和顺式作用调控区进行了全面测序。在来自三个独立地点的家庭中的2000多名参与者的样本中，我们对五个候选风险基因（DNAAF4、CYP19A1、DCDC2、KIAA0319和GRIN2B）的所有外显子和一些调控元件进行了靶向捕获和全面测序，此前已有多个样本提供了这些基因在阅读障碍中起作用的证据。我们使用个体常见单核苷酸多态性和聚集的罕见变异评估了六种与阅读障碍相关的定量表型（性状）中每一种的关联证据。我们在编码外显子中未检测到启动子改变，有害变异也很少，其中没有一个显示出与任何性状相关的证据。DNAAF4的单变异和聚集检测未能检测到与任何性状相关的显著证据。其他四个基因提供了与一种或多种性状相关的证据。CYP19A1下游的一个常见变异显示出与多种性状相关的显著证据，无论是否进行言语智商（VIQ）调整。一个从KIAA0319下游区域延伸到DCDC2第二个内含子的单倍型与限时真实单词阅读表现降低有关。最后，GRIN2B中的罕见外显子变异与拼写表现相关，无论是否进行VIQ调整。我们从这项大规模测序研究中得到的结果补充了全基因组关联研究的结果，反对这五个候选基因中存在大效应编码变异的致病作用，支持多基因病因，并表明转录调控的作用。
