Il Bin Kim1,2,21, Taeyeop Lee1,3,4,21, Junehawk Lee5,21, Jonghun Kim6, Suho Lee7, In Gyeong Koh8, Jae Hyun Kim9,10,11, Joon-Yong An9,10,11, Hyunseong Lee12, Woo Kyeong Kim1, Young Seok Ju1, Yongseong Cho5, Seok Jong Yu5, Soon Ae Kim13, Miae Oh14, Dong Wook Han15,16, Eunjoon Kim7,17,*, Jung Kyoon Choi3,*, Hee Jeong Yoo18,19,* and Jeong Ho Lee1,20,*
1Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. 2Department of Psychiatry, Hanyang University Guri Hospital, Guri 11923, Republic of Korea. 3Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. 4Department of Psychiatry, University of Ulsan College of Medicine, Asan Medical Center, Seoul 05505, Republic of Korea. 5Center for Supercomputing Applications, Division of National Supercomputing, Korea Institute of Science and Technology Information, Daejeon 34141, Republic of Korea. 6Department of Genetics, Yale Stem Cell Center, Yale Child Study Center, Yale School of Medicine, New Haven, CT 06520, USA. 7Center for Synaptic Brain Dysfunctions, Institute for Basic Science, Daejeon 34141, Republic of Korea. 8Industry-University Cooperation Foundation, Hanyang University, Seoul 04763, Republic of Korea. 9Department of Integrated Biomedical and Life Science, Korea University, Seoul 02841, Republic of Korea. 10BK21FOUR R&E Center for Learning Health Systems, Korea University, Seoul 02841, Republic of Korea. 11School of Biosystem and Biomedical Science, College of Health Science, Korea University, Seoul 02841, Republic of Korea. 12Department of Stem Cell Biology, School of Medicine, Konkuk University, Seoul 05030, Republic of Korea. 13Department of Pharmacology, Eulji University, Daejeon 13135, Republic of Korea. 14Department of Psychiatry, Kyung Hee University Hospital, Seoul 02447, Republic of Korea. 15School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China. 16Organoid sciences, Ltd., Bundang-gu, Seongnam 13488, Republic of Korea. 17Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. 18Department of Psychiatry, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea. 19Department of Psychiatry, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. 20Sovargen Co. Ltd., Daejeon 34051, Republic of Korea. 21These authors contributed equally: Il Bin Kim, Taeyeop Lee, Junehawk Lee.
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.