Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk

Takumi Nakamura; Junko Ueda; Shota Mizuno; Kurara Honda; An-A Kazuno; Hirona Yamamoto; Tomonori Hara; Atsushi Takata

doi:10.1016/j.xgen.2024.100488

Topologically associating domains define the impact of de novo promoter variants on autism spectrum disorder risk

Cell Genom. 2024 Feb 14;4(2):100488. doi: 10.1016/j.xgen.2024.100488. Epub 2024 Jan 26.

Authors

Takumi Nakamura¹, Junko Ueda², Shota Mizuno¹, Kurara Honda¹, An-A Kazuno¹, Hirona Yamamoto³, Tomonori Hara⁴, Atsushi Takata⁵

Affiliations

¹ Laboratory for Molecular Pathology of Psychiatric Disorders, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
² Laboratory for Molecular Pathology of Psychiatric Disorders, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Electronic address: junko.hayashi.aa@riken.jp.
³ Laboratory for Molecular Pathology of Psychiatric Disorders, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8654, Japan.
⁴ Laboratory for Molecular Pathology of Psychiatric Disorders, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Department of Organ Anatomy, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.
⁵ Laboratory for Molecular Pathology of Psychiatric Disorders, RIKEN Center for Brain Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan; Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: atsushi.takata@riken.jp.

Abstract

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.

Keywords: ASD; CRISPR-Cas9; CTCF; TAD; de novo variant; enhancer release and retargeting; human iPSC; promoter; regulatory element; whole-genome sequencing.

MeSH terms

Autism Spectrum Disorder* / genetics
Gene Expression Regulation
Genetic Predisposition to Disease / genetics
Humans
Induced Pluripotent Stem Cells*
Whole Genome Sequencing