The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
Nat Genet. 2019 Mar;51(3):431-444. doi: 10.1038/s41588-019-0344-8. Epub 2019 Feb 25.
Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD.
自闭症谱系障碍（ASD）是一组高度遗传和异质性的神经发育表型，在超过 1%的儿童中被诊断出来。常见的遗传变异对 ASD 的易感性有很大贡献，但迄今为止，没有任何个体变异与 ASD 有明显的关联。利用来自独特的丹麦人群资源的显著样本量增加，我们对 18381 名 ASD 患者和 27969 名对照进行了全基因组关联荟萃分析，确定了五个全基因组显著位点。利用与具有显著重叠遗传结构的三种表型（精神分裂症、重度抑郁症和教育程度）的 GWAS 结果，我们在同样严格的显著性水平上发现了与其他特征共有的七个额外位点。剖析多基因结构，我们发现 ASD 亚型之间存在数量和质量上的多基因异质性。这些结果突出了生物学上的见解，特别是与神经元功能和皮质发生有关，并确立了在不久的将来，大规模进行的 GWAS 在 ASD 方面将更有成效。
