Methodological advances over the last three decades have led to a profound transformation in our understanding of the genetic origins of neuropsychiatric disorders. This is exemplified by the study of autism spectrum disorders (ASDs) for which microarrays, whole exome sequencing and whole genome sequencing have yielded over a hundred causal loci. Genome-wide association studies in ASD have also been fruitful, identifying 5 genome-wide significant loci thus far and demonstrating a substantial role for polygenic inherited risk. Approaches rooted in systems biology and functional genomics have increasingly placed genes implicated by risk variants into biological context. Genetic risk affects a finite group of cell-types and biological processes, converging primarily on early stages of brain development (though, the expression of many risk genes persists through childhood). Coupled with advances in stem cell-based human in vitro model systems, these findings provide a basis for developing mechanistic models of disease pathophysiology.

中文翻译：

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自闭症谱系障碍遗传学的三十年：为神经生物学理解和治疗奠定基础


过去三十年方法论的进步使我们对神经精神疾病遗传起源的理解发生了深刻的转变。自闭症谱系障碍 (ASD) 的研究就是例证，针对该疾病，微阵列、全外显子组测序和全基因组测序已经产生了一百多个因果位点。 ASD 的全基因组关联研究也取得了丰硕的成果，迄今为止确定了 5 个全基因组显着位点，并证明了多基因遗传风险的重要作用。植根于系统生物学和功能基因组学的方法越来越多地将与风险变异相关的基因置于生物学背景中。遗传风险影响有限的一组细胞类型和生物过程，主要集中在大脑发育的早期阶段（尽管许多风险基因的表达在整个童年时期持续存在）。结合基于干细胞的人体体外模型系统的进展，这些发现为开发疾病病理生理学机制模型提供了基础。