Autism spectrum disorder (ASD) affects 1% of world population and has become a pressing medical and social problem worldwide. As a paradigmatic complex genetic disease, ASD has been intensively studied and thousands of gene mutations have been reported. Because these mutations rarely recur, it is difficult to (i) pinpoint the fewer disease-causing versus majority random events and (ii) replicate or verify independent studies. A coherent and systematic understanding of autism biology has not been achieved. We analyzed 3392 and 4792 autism-related mutations from two large-scale whole-exome studies across multiple resolution levels, that is, variants (single-nucleotide), genes (protein-coding unit), and pathways (molecular module). These mutations do not recur or replicate at the variant level, but significantly and increasingly do so at gene and pathway levels. Genetic association reveals a novel gene + pathway dual-hit model, where the mutation burden becomes less relevant. In multiple independent analyses, hundreds of variants or genes repeatedly converge to several canonical pathways, either novel or literature-supported. These pathways define recurrent and systematic ASD biology, distinct from previously reported gene groups or networks. They also present a catalog of novel ASD risk factors including 118 variants and 72 genes. At a subpathway level, most variants disrupt the pathway-related gene functions, and in the same gene, they tend to hit residues extremely close to each other and in the same domain. Multiple interacting variants spotlight key modules, including the cAMP (adenosine 3',5'-monophosphate) second-messenger system and mGluR (metabotropic glutamate receptor) signaling regulation by GRKs (G protein-coupled receptor kinases). At a superpathway level, distinct pathways further interconnect and converge to three biology themes: synaptic function, morphology, and plasticity.

中文翻译：

---

从大量的基因突变概况系统地重建自闭症生物学。

自闭症谱系障碍（ASD）影响世界1％的人口，并已成为世界范围内紧迫的医学和社会问题。作为一种典型的复杂遗传病，对ASD进行了深入研究，并报道了成千上万的基因突变。由于这些突变很少复发，因此很难（i）查明与大多数随机事件相比较少的致病原因，以及（ii）复制或验证独立研究。尚未实现对自闭症生物学的连贯和系统的理解。我们分析了来自两个大规模全外显子研究的3392和4792孤独症相关突变，这些研究涉及多个分辨率水平，即变异体（单核苷酸），基因（蛋白质编码单位）和途径（分子模块）。这些突变不会在变体水平上重复出现或复制，但在基因和途径水平上却越来越重要。遗传关联揭示了一种新型的基因+途径双重打击模型，其中突变负担变得不那么重要。在多个独立的分析中，数百个变体或基因反复收敛到几种经典的途径，无论是新颖的还是文献支持的。这些途径定义了复发性和系统性的ASD生物学，不同于先前报道的基因组或网络。他们还提出了新的ASD危险因素的目录，包括118个变体和72个基因。在亚途径水平上，大多数变体破坏了与途径相关的基因功能，并且在同一基因中，它们倾向于击中彼此极为靠近且位于同一域的残基。多个相互作用的变体聚焦了关键模块，包括cAMP（腺苷3'，5' -单磷酸）第二信使系统和mGluR（代谢型谷氨酸受体）通过GRKs（G蛋白偶联受体激酶）进行信号传导调节。在超级途径水平上，不同的途径进一步相互联系并融合为三个生物学主题：突触功能，形态和可塑性。