RT Journal Article SR Electronic T1 Noncoding de novo mutations contribute to autism spectrum disorder via chromatin interactions JF bioRxiv FD Cold Spring Harbor Laboratory SP 2019.12.15.877324 DO 10.1101/2019.12.15.877324 A1 Il Bin Kim A1 Taeyeop Lee A1 Junehawk Lee A1 Jonghun Kim A1 Hyunseong Lee A1 Woo Kyeong Kim A1 Young Seok Ju A1 Yongseong Cho A1 Seok Jong Yu A1 Soon Ae Kim A1 Miae Oh A1 Tae Hwan Kwak A1 Sai Hali A1 Dong Wook Han A1 Eunjoon Kim A1 Jung Kyoon Choi A1 Hee Jeong Yoo A1 Jeong Ho Lee YR 2019 UL http://biorxiv.org/content/early/2019/12/16/2019.12.15.877324.abstract AB Three-dimensional chromatin structures regulate gene expression across genome. The significance of de novo mutations (DNMs) affecting chromatin interactions in autism spectrum disorder (ASD) remains poorly understood. We generated 931 whole-genome sequences for Korean simplex families to detect DNMs and identified target genes dysregulated by noncoding DNMs via long-range chromatin interactions between regulatory elements. Notably, noncoding DNMs that affect chromatin interactions exhibited transcriptional dysregulation implicated in ASD risks. Correspondingly, target genes were significantly involved in histone modification, prenatal brain development, and pregnancy. Both noncoding and coding DNMs collectively contributed to low IQ in ASD. Indeed, noncoding DNMs resulted in alterations, via chromatin interactions, in target gene expression in primitive neural stem cells derived from human induced pluripotent stem cells from an ASD subject. The emerging neurodevelopmental genes, not previously implicated in ASD, include CTNNA2, GRB10, IKZF1, PDE3B, and BACE1. Our results were reproducible in 517 probands from MSSNG cohort. This work demonstrates that noncoding DNMs contribute to ASD via chromatin interactions.