Genetic contributions to autism spectrum disorder.
Genetic contributions to autism spectrum disorder.
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DOI：
10.1017/s0033291721000192
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发表时间：
2021-10
影响因子：
6.9
通讯作者：
Warrier V
中科院分区：
文献类型：
--
作者：
Havdahl A;Niarchou M;Starnawska A;Uddin M;van der Merwe C;Warrier V
自闭症谱系障碍（Autism spectrum disorder，Autism）是一组异质性的神经发育疾病，其特征是儿童早期在交流和社会互动方面出现障碍，同时存在限制性和重复性的行为和兴趣。这篇综述总结了人类遗传学研究自闭症的最新进展，辅之以表观遗传学和转录组学的研究结果。自闭症的临床异质性反映在一个复杂的遗传结构中，涉及几种常见和罕见的变异，从点突变到大拷贝数变异，以及遗传或自发（从头）。在高度受限的基因中，有100多个风险基因与罕见的、通常是从头发生的、潜在的破坏性突变有关。这些风险占个人风险的很大一部分，但占人口风险的一小部分。相比之下，大多数遗传风险可归因于共同的遗传变异，每种变异都有很小的影响。研究已经确定了一些强烈相关的常见变异。不同的风险基因在相同的机制上趋同，如基因调控和突触连接。这些机制也与自闭症中表观遗传和转录失调的基因有关。理解生物学机制的主要挑战包括大量的表型异质性、大的基因座异质性、可变的等位基因率和广泛的多效性。为了更好地了解所涉及的数百或数千种常见和罕见的遗传变异，需要大量增加样本量。未来的研究应该整合常见和罕见变异研究，包括基因组学，表观基因组学和转录组学在内的多组学数据，以及多维和纵向测量的精细表型评估。
Autism spectrum disorder (autism) is a heterogeneous group of neurodevelopmental conditions characterized by early childhood-onset impairments in communication and social interaction alongside restricted and repetitive behaviors and interests. This review summarizes recent developments in human genetics research in autism, complemented by epigenetic and transcriptomic findings. The clinical heterogeneity of autism is mirrored by a complex genetic architecture involving several types of common and rare variants, ranging from point mutations to large copy number variants, and either inherited or spontaneous (de novo). More than 100 risk genes have been implicated by rare, often de novo, potentially damaging mutations in highly constrained genes. These account for substantial individual risk but a small proportion of the population risk. In contrast, most of the genetic risk is attributable to common inherited variants acting en masse, each individually with small effects. Studies have identified a handful of robustly associated common variants. Different risk genes converge on the same mechanisms, such as gene regulation and synaptic connectivity. These mechanisms are also implicated by genes that are epigenetically and transcriptionally dysregulated in autism. Major challenges to understanding the biological mechanisms include substantial phenotypic heterogeneity, large locus heterogeneity, variable penetrance, and widespread pleiotropy. Considerable increases in sample sizes are needed to better understand the hundreds or thousands of common and rare genetic variants involved. Future research should integrate common and rare variant research, multi-omics data including genomics, epigenomics, and transcriptomics, and refined phenotype assessment with multidimensional and longitudinal measures.