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Noncoding de novo mutations contribute to autism via long-range chromatin interactions

Published online by Cambridge University Press:  19 July 2023

I. B. Kim ,
J. Choi ,
J. E. Park ,
J.-C. Lee  and
S.-B. Jung
I. B. Kim*
Affiliation:
Hanyan University Medical College, Seoul
J. Choi
Affiliation:
Hanyan University Medical College, Seoul
J. E. Park
Affiliation:
Keyo Hospital, Uiwang, Korea, Republic Of
J.-C. Lee
Affiliation:
Keyo Hospital, Uiwang, Korea, Republic Of
S.-B. Jung
Affiliation:
Keyo Hospital, Uiwang, Korea, Republic Of
*
*Corresponding author.

Abstract

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Introduction

Three-dimensional chromatin interactions regulate gene expressions. The significance of de novo mutations (DNMs) in chromatin interactions remains poorly understood for autism spectrum disorder (ASD).

Objectives

To investigate the genomic architecture of ASD in terms of non-coding de novo mutations and 3-dimensional chromatin interactions

Methods

We generated 813 whole-genome sequences from 242 Korean simplex families to detect DNMs, and identified target genes which were putatively affected by non-coding DNMs in chromatin interactions.

Results

Non-coding DNMs in chromatin interactions were significantly involved in transcriptional dysregulations related to ASD risk. Correspondingly, target genes showed spatiotemporal expressions relevant to ASD in developing brains and enrichment in biological pathways implicated in ASD, such as histone modification. Regarding clinical features of ASD, non-coding DNMs in chromatin interactions particularly contributed to low intelligence quotient levels in ASD probands. We further validated our findings using two replication cohorts, Simons Simplex Collection (SSC) and MSSNG, and showed the consistent enrichment of non-coding DNM-disrupted chromatin interactions in ASD probands. Generating human induced pluripotent stem cells in two ASD families, we were able to demonstrate that non-coding DNMs in chromatin interactions alter the expression of target genes at the stage of early neural development.

Conclusions

Taken together, our findings indicate that non-coding DNMs in ASD probands lead to early neurodevelopmental disruption implicated in ASD risk via chromatin interactions.

Disclosure of Interest

None Declared

Type
Abstract
Information
European Psychiatry , Volume 66 , Special Issue S1: Abstracts of the 31st European Congress of Psychiatry , March 2023 , pp. S350 - S351
Creative Commons
Creative Common License - CCCreative Common License - BY
This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
Copyright
© The Author(s), 2023. Published by Cambridge University Press on behalf of the European Psychiatric Association
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