Multivariate genome-wide association analysis of quantitative reading skill and dyslexia improves gene discovery
Multivariate genome-wide association analysis of quantitative reading skill and dyslexia improves gene discovery
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DOI：
10.1101/2024.02.15.24302884
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发表时间：
2024-02
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通讯作者：
H. S. Mountford;E. Eising;P. Fontanillas;A. Auton;23andMe Research Team;E. K. Irving-Pease;C. Doust;T. C. Bates;N. G. Martin;S. E. Fisher;M. Luciano
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作者：
H. S. Mountford;E. Eising;P. Fontanillas;A. Auton;23andMe Research Team;E. K. Irving-Pease;C. Doust;T. C. Bates;N. G. Martin;S. E. Fisher;M. Luciano
阅读能力是一项重要的生活技能，也是接受教育的主要途径。阅读能力的个体差异受到遗传变异的影响，根据双胞胎研究估计，单词阅读的遗传率为0.66。直到最近，基因组研究还受限于适度的样本量。在这里，我们使用多变量全基因组关联研究（GWAS）方法，MTAG，利用两个独立的GWAS研究的汇总统计数据，提高了分析阅读能力的能力；GenLang的单词阅读meta分析（N = 27 180）和23andMe， Inc.的阅读障碍研究（Ncases = 51 800， n对照= 1 087 070）。我们将有效样本量增加到N = 102 082，这代表了迄今为止最大的阅读能力基因研究。我们确定了35个独立的全基因组显著位点，包括7个以前未报道的区域。单核苷酸多态性（SNP）遗传率估计为24%。我们观察到认知和教育措施明显的正相关遗传。基因集分析涉及神经元突触和前神经胶质母细胞瘤通路，进一步支持了发育中的胚胎脑中神经元表达基因的富集。在国家儿童发展研究队列（N = 6410）的独立样本中，我们的多变量结果的多基因得分预测阅读能力的方差在2.29-3.50%之间。多基因适应研究使用了跨越近1.5万年前的大量古代基因组。我们没有发现选择的证据，这表明欧洲人的阅读能力可能不受最近的选择压力的影响。通过结合现有数据集来提高统计能力，这些结果为阅读生物学提供了新的见解。
The ability to read is an important life skill and a major route to education. Individual differences in reading ability are influenced by genetic variation, with a heritability of 0.66 for word reading, estimated by twin studies. Until recently, genomic investigations were limited by modest sample size. Here we use a multivariate genome-wide association study (GWAS) method, MTAG, to leverage summary statistics from two independent GWAS efforts, boosting power for analyses of reading ability; GenLang meta-analysis of word reading (N = 27 180) and the 23andMe, Inc., study of dyslexia (Ncases = 51 800, Ncontrols = 1 087 070). We increase effective sample size to N = 102 082, representing the largest genetic study of reading ability, to date. We identified 35 independent genome-wide significant loci, including 7 regions not previously reported. Single-nucleotide polymorphism (SNP) based heritability was estimated at 24%. We observed clear positive genetic correlations with cognitive and educational measures. Gene-set analyses implicated neuronal synapses and proneural glioblastoma pathways, further supported by enrichment of neuronally expressed genes in the developing embryonic brain. Polygenic scores of our multivariate results predicted between 2.29-3.50% of variance in reading ability in an independent sample, the National Child Development Study cohort (N = 6 410). Polygenic adaptation was examined using a large panel of ancient genomes spanning the last ~15k years. We did not find evidence of selection, suggesting that reading ability may not have been subject to recent selection pressure in Europeans. By combining existing datasets to improve statistical power, these results provide novel insights into the biology of reading.