Genetic neurodevelopmental clustering and dyslexia
Genetic neurodevelopmental clustering and dyslexia
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DOI：
10.1101/2023.10.04.23296530
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发表时间：
2023-10
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影响因子：
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通讯作者：
Austeja Ciulkinyte;H. Mountford;P. Fontanillas;Research Team;Timothy C. Bates;Nicholas G Martin;Simon E. Fisher;Michelle Luciano
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文献类型：
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作者：
Austeja Ciulkinyte;H. Mountford;P. Fontanillas;Research Team;Timothy C. Bates;Nicholas G Martin;Simon E. Fisher;Michelle Luciano
阅读障碍是一种源于神经发育的学习困难，表现为尽管接受了适当的教育，但阅读和拼写的准确性和速度都有所下降。阅读障碍在很大程度上是可遗传的，经常与其他神经发育疾病，特别是注意力缺陷多动障碍(ADHD)并存。这篇文章的目的是阐明易患阅读障碍的遗传因素与其他神经发育和精神特征的风险之间的关系。采用基因组结构方程模型(GenomicSEM)对大规模的阅读障碍诊断自报(51800例和110万名对照)以及ADHD、自闭症、抽动症、焦虑、抑郁、精神分裂症、躁郁症、强迫症、厌食症等疾病进行全基因组关联研究，构建基因组结构模型。最终的模型由五个相关的潜在基因组因素组成，分别是F1)内化障碍，F2)精神障碍，F3)强迫症，F4)神经发育状况，F5)注意力和学习困难，包括ADHD和阅读障碍。这种潜在因素与内在性障碍(0.40)有适度的相关性，在较小程度上与神经发育状况(0.25)和精神障碍(0.17)相关，与强迫症(-0.16)呈负相关。与ADHD不同，阅读障碍的大多数基因组变异都是独一无二的，这表明与精神特征的关系更微不足道。我们进一步研究了阅读困难和ADHD的遗传变异。这涉及到49个座位(其中40个没有在个体性状的GWA中报道)映射到174个基因(121个在个体性状的GWA中没有发现)。我们的研究发现了新的多效性变异，并通过基因组扫描电子显微镜证实了阅读困难和ADHD与其他精神特征之间的高度遗传联系。未来，包括计算障碍和运动障碍等其他共生特征的分析，将允许对注意力和学习困难的基因组因素有更明确的定义，从而进一步深入了解因素结构和多效性效应。
Dyslexia is a learning difficulty with neurodevelopmental origins, manifesting as reduced accuracy and speed in reading and spelling despite adequate education. Dyslexia is substantially heritable and frequently co-occurs with other neurodevelopmental conditions, particularly attention deficit-hyperactivity disorder (ADHD). The purpose of this paper was to elucidate how genetic factors predisposing to dyslexia correlate with risk for other neurodevelopmental and psychiatric traits. A large-scale genome-wide association study (GWAS) of dyslexia diagnosis self-report (51,800 cases and ~1.1 million controls), together with GWAS of ADHD, autism, Tourette syndrome, anxiety, depression, schizophrenia, bipolar, obsessive compulsive disorder, anorexia, were analysed using Genomic Structural Equation Modelling (GenomicSEM) to construct a genomic structural model. The final model consisted of five correlated latent genomic factors described as F1) internalising disorders, F2) psychotic disorders, F3) compulsive disorders, F4) neurodevelopmental conditions, and F5) attention and learning difficulties, which includes ADHD and dyslexia. This latent factor was moderately correlated with internalising disorders (.40) and, to a lesser extent, with neurodevelopmental conditions (.25) and psychotic disorders (.17), and negatively with compulsive disorders (-.16). Unlike ADHD, most of the genomic variance in dyslexia was unique, suggesting a more peripheral relation to psychiatric traits. We further investigated genetic variants underlying both dyslexia and ADHD. This implicated 49 loci (40 of which were not reported in GWAS of the individual traits) mapping to 174 genes (121 not found in GWAS of individual traits). Our study has discovered novel pleiotropic variants and confirms via GenomicSEM the heightened genetic relation between dyslexia and ADHD versus other psychiatric traits. In future, analyses including additional co-occurring traits such as dyscalculia and dyspraxia, for which there are currently no large-scale GWAS, will allow a more clear definition of the attention and learning difficulties genomic factor, yielding further insights into factor structure and pleiotropic effects.