Laboratory for Molecular Pathology of Psychiatric Disorders, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Laboratory for Molecular Pathology of Psychiatric Disorders, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Cell Genom. 2024 Feb 14;4(2):100488. doi: 10.1016/j.xgen.2024.100488. Epub 2024 Jan 26.
Whole-genome sequencing (WGS) studies of autism spectrum disorder (ASD) have demonstrated the roles of rare promoter de novo variants (DNVs). However, most promoter DNVs in ASD are not located immediately upstream of known ASD genes. In this study analyzing WGS data of 5,044 ASD probands, 4,095 unaffected siblings, and their parents, we show that promoter DNVs within topologically associating domains (TADs) containing ASD genes are significantly and specifically associated with ASD. An analysis considering TADs as functional units identified specific TADs enriched for promoter DNVs in ASD and indicated that common variants in these regions also confer ASD heritability. Experimental validation using human induced pluripotent stem cells (iPSCs) showed that likely deleterious promoter DNVs in ASD can influence multiple genes within the same TAD, resulting in overall dysregulation of ASD-associated genes. These results highlight the importance of TADs and gene-regulatory mechanisms in better understanding the genetic architecture of ASD.
全基因组测序（WGS）研究表明，自闭症谱系障碍（ASD）与罕见的启动子新生变异（DNV）有关。然而，ASD 中的大多数启动子 DNV 并不位于已知的 ASD 基因的上游。在这项对 5044 名 ASD 先证者、4095 名无相关兄弟姐妹及其父母的 WGS 数据分析研究中，我们表明 ASD 基因所在的拓扑关联域（TAD）内的启动子 DNV 与 ASD 显著相关。考虑到 TAD 作为功能单元的分析确定了 ASD 中富含启动子 DNV 的特定 TAD，并表明这些区域的常见变异也可导致 ASD 的遗传力。使用人类诱导多能干细胞（iPSC）进行的实验验证表明，ASD 中的可能有害的启动子 DNV 可影响同一 TAD 内的多个基因，导致 ASD 相关基因的整体失调。这些结果突出了 TAD 和基因调控机制在更好地理解 ASD 遗传结构方面的重要性。
