PDF(Pubmed)
Abstract：
Reading disorders (RD) are human-specific neuropsychological conditions associated with decoding printed words and/or reading comprehension. So far only a handful of candidate genes segregated in families and 42 loci from genome-wide association study (GWAS) have been identified that jointly provided little clues of pathophysiology. Leveraging human-specific genomic information, we critically assessed the RD candidates for the first time and found substantial human-specific features within. The GWAS candidates (i.e., population signals) were distinct from the familial counterparts and were more likely pleiotropic in neuropsychiatric traits and to harbor human-specific regulatory elements (HSREs). Candidate genes associated with human cortical morphology indeed showed human-specific expression in adult brain cortices, particularly in neuroglia likely regulated by HSREs. Expression levels of candidate genes across human brain developmental stages showed a clear pattern of uplifted expression in early brain development crucial to RD development. Following the new insights and loci pleiotropic in cognitive traits, we identified four novel genes from the GWAS sub-significant associations (i.e., FOXO3, MAPT, KMT2E and HTT) and the Semaphorin gene family with functional priors (i.e., SEMA3A, SEMA3E and SEMA5B). These novel genes were related to neuronal plasticity and disorders, mostly conserved the pattern of uplifted expression in early brain development and had evident expression in cortical neuroglial cells. Our findings jointly illuminated the association of RD with neuroglia regulation-an emerging hotspot in studying neurodevelopmental disorders, and highlighted the need of improving RD phenotyping to avoid jeopardizing future genetic studies of RD.
摘要：
阅读障碍（RD）是与解码印刷单词和/或阅读理解相关的人类特异性神经心理状况。到目前为止，只有少数在家族中分离的候选基因和来自全基因组关联研究（GWAS）的42个基因座被确定，它们共同提供了很少的病理生理学线索。利用人类特有的基因组信息，我们首次对RD候选者进行了批判性评估,并在其中发现了大量的人类特异性特征.GWAS候选人(即，人口信号）与家族对应物不同，并且更可能在神经精神特征上具有多效性，并且具有人类特异性调节元件（HSRE）。与人类大脑皮层形态相关的候选基因确实在成人大脑皮层中显示出人类特异性表达，特别是在可能由HSREs调节的神经胶质细胞中。在整个人脑发育阶段中候选基因的表达水平显示出在对RD发育至关重要的早期脑发育中表达上调的清晰模式。在认知特征的新见解和基因座多效性之后，我们从GWAS亚显著关联中鉴定了四个新基因(即，FOXO3，MAPT，KMT2E和HTT）和具有功能先验的信号素基因家族（即，SEMA3A,SEMA3E和SEMA5B）。这些新基因与神经元可塑性和疾病有关，大多数保留了早期脑发育中表达升高的模式，并且在皮质神经胶质细胞中具有明显的表达。我们的发现共同阐明了RD与神经胶质细胞调节的关联-这是研究神经发育障碍的新兴热点。并强调需要改进RD表型，以避免危及未来RD的遗传研究。
