Non-coding de novo mutations in chromatin interactions are implicated in autism spectrum disorder

Il Bin Kim; Taeyeop Lee; Junehawk Lee; Jonghun Kim; Suho Lee; In Gyeong Koh; Jae Hyun Kim; Joon Yong An; Hyunseong Lee; Woo Kyeong Kim; Young Seok Ju; Yongseong Cho; Seok Jong Yu; Soon Ae Kim; Miae Oh; Dong Wook Han; Eunjoon Kim; Jung Kyoon Choi; Hee Jeong Yoo; Jeong Ho Lee

doi:10.1038/s41380-022-01697-2

Non-coding de novo mutations in chromatin interactions are implicated in autism spectrum disorder

Il Bin Kim, Taeyeop Lee, Junehawk Lee, Jonghun Kim, Suho Lee, In Gyeong Koh, Jae Hyun Kim, Joon Yong An, Hyunseong Lee, Woo Kyeong Kim, Young Seok Ju, Yongseong Cho, Seok Jong Yu, Soon Ae Kim, Miae Oh, Dong Wook Han, Eunjoon Kim, Jung Kyoon Choi, Hee Jeong Yoo, Jeong Ho Lee

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

Abstract

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

Original language	English
Pages (from-to)	4680-4694
Number of pages	15
Journal	Molecular Psychiatry
Volume	27
Issue number	11
DOIs	https://doi.org/10.1038/s41380-022-01697-2
Publication status	Published - 2022 Nov

Bibliographical note

Funding Information:
This work was supported by grants from the Suh Kyungbae Foundation (to JHL); the National Research Foundation of Korea funded by the Korea government, Ministry of Science and ICT (2019R1A3B2066619 to JHL); Brain Research Program through National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2017M3C7A1048089 to JKC); Original Technology Research Program for Brain Science of the NRF, funded by the Korean government, MIST (2017M3C7A1027467 to HJY; 2020R1C1C1003426 to JYA; 2021M3E5D9021878 to HJY); Research grant from Seoul National University Bundang Hospital (14–2015-011 to HJY); Institute for Basic Science (IBS) (IBS-R002-D1 to EK); Korea Institute of Science and Technology Information (K-19-L02-C07 to JL, YC, and SJY); Bio & Medical Technology Development Program of the National Research Foundation of Korea funded by the Ministry of Health and Welfare, Ministry of Science and ICT, Ministry of Trade Industry and Energy, Korea Disease Control and Prevention Agency (The National Project of Bio Big Data) (NRF-2020M3E5D7085175 to IBK).

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41380-022-01697-2

Cite this

Kim, I. B., Lee, T., Lee, J., Kim, J., Lee, S., Koh, I. G., Kim, J. H., An, J. Y., Lee, H., Kim, W. K., Ju, Y. S., Cho, Y., Yu, S. J., Kim, S. A., Oh, M., Han, D. W., Kim, E., Choi, J. K., Yoo, H. J., & Lee, J. H. (2022). Non-coding de novo mutations in chromatin interactions are implicated in autism spectrum disorder. Molecular Psychiatry, 27(11), 4680-4694. https://doi.org/10.1038/s41380-022-01697-2

Kim, IB, Lee, T, Lee, J, Kim, J, Lee, S, Koh, IG, Kim, JH, An, JY, Lee, H, Kim, WK, Ju, YS, Cho, Y, Yu, SJ, Kim, SA, Oh, M, Han, DW, Kim, E, Choi, JK, Yoo, HJ & Lee, JH 2022, 'Non-coding de novo mutations in chromatin interactions are implicated in autism spectrum disorder', Molecular Psychiatry, vol. 27, no. 11, pp. 4680-4694. https://doi.org/10.1038/s41380-022-01697-2

@article{4dc01504d86745ea8c63fe99015d1b44,

title = "Non-coding de novo mutations in chromatin interactions are implicated in autism spectrum disorder",

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

author = "Kim, {Il Bin} and Taeyeop Lee and Junehawk Lee and Jonghun Kim and Suho Lee and Koh, {In Gyeong} and Kim, {Jae Hyun} and An, {Joon Yong} and Hyunseong Lee and Kim, {Woo Kyeong} and Ju, {Young Seok} and Yongseong Cho and Yu, {Seok Jong} and Kim, {Soon Ae} and Miae Oh and Han, {Dong Wook} and Eunjoon Kim and Choi, {Jung Kyoon} and Yoo, {Hee Jeong} and Lee, {Jeong Ho}",

note = "Funding Information: This work was supported by grants from the Suh Kyungbae Foundation (to JHL); the National Research Foundation of Korea funded by the Korea government, Ministry of Science and ICT (2019R1A3B2066619 to JHL); Brain Research Program through National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2017M3C7A1048089 to JKC); Original Technology Research Program for Brain Science of the NRF, funded by the Korean government, MIST (2017M3C7A1027467 to HJY; 2020R1C1C1003426 to JYA; 2021M3E5D9021878 to HJY); Research grant from Seoul National University Bundang Hospital (14–2015-011 to HJY); Institute for Basic Science (IBS) (IBS-R002-D1 to EK); Korea Institute of Science and Technology Information (K-19-L02-C07 to JL, YC, and SJY); Bio & Medical Technology Development Program of the National Research Foundation of Korea funded by the Ministry of Health and Welfare, Ministry of Science and ICT, Ministry of Trade Industry and Energy, Korea Disease Control and Prevention Agency (The National Project of Bio Big Data) (NRF-2020M3E5D7085175 to IBK). Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2022",

month = nov,

doi = "10.1038/s41380-022-01697-2",

language = "English",

volume = "27",

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journal = "Molecular Psychiatry",

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T1 - Non-coding de novo mutations in chromatin interactions are implicated in autism spectrum disorder

AU - Kim, Il Bin

AU - Lee, Taeyeop

AU - Lee, Junehawk

AU - Kim, Jonghun

AU - Lee, Suho

AU - Koh, In Gyeong

AU - Kim, Jae Hyun

AU - An, Joon Yong

AU - Lee, Hyunseong

AU - Kim, Woo Kyeong

AU - Ju, Young Seok

AU - Cho, Yongseong

AU - Yu, Seok Jong

AU - Kim, Soon Ae

AU - Oh, Miae

AU - Han, Dong Wook

AU - Kim, Eunjoon

AU - Choi, Jung Kyoon

AU - Yoo, Hee Jeong

AU - Lee, Jeong Ho

N1 - Funding Information: This work was supported by grants from the Suh Kyungbae Foundation (to JHL); the National Research Foundation of Korea funded by the Korea government, Ministry of Science and ICT (2019R1A3B2066619 to JHL); Brain Research Program through National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (2017M3C7A1048089 to JKC); Original Technology Research Program for Brain Science of the NRF, funded by the Korean government, MIST (2017M3C7A1027467 to HJY; 2020R1C1C1003426 to JYA; 2021M3E5D9021878 to HJY); Research grant from Seoul National University Bundang Hospital (14–2015-011 to HJY); Institute for Basic Science (IBS) (IBS-R002-D1 to EK); Korea Institute of Science and Technology Information (K-19-L02-C07 to JL, YC, and SJY); Bio & Medical Technology Development Program of the National Research Foundation of Korea funded by the Ministry of Health and Welfare, Ministry of Science and ICT, Ministry of Trade Industry and Energy, Korea Disease Control and Prevention Agency (The National Project of Bio Big Data) (NRF-2020M3E5D7085175 to IBK). Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2022/11

Y1 - 2022/11

N2 - 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). 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. 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. Taken together, our findings indicate that non-coding DNMs in ASD probands lead to early neurodevelopmental disruption implicated in ASD risk via chromatin interactions.

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

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ER -

Non-coding de novo mutations in chromatin interactions are implicated in autism spectrum disorder

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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