Three-dimensional physical interactions within chromosomes dynamically regulate gene expression in a tissue-specific manner1,2,3. However, the 3D organization of chromosomes during human brain development and its role in regulating gene networks dysregulated in neurodevelopmental disorders, such as autism or schizophrenia4,5,6, are unknown. Here we generate high-resolution 3D maps of chromatin contacts during human corticogenesis, permitting large-scale annotation of previously uncharacterized regulatory relationships relevant to the evolution of human cognition and disease. Our analyses identify hundreds of genes that physically interact with enhancers gained on the human lineage, many of which are under purifying selection and associated with human cognitive function. We integrate chromatin contacts with non-coding variants identified in schizophrenia genome-wide association studies (GWAS), highlighting multiple candidate schizophrenia risk genes and pathways, including transcription factors involved in neurogenesis, and cholinergic signalling molecules, several of which are supported by independent expression quantitative trait loci and gene expression analyses. Genome editing in human neural progenitors suggests that one of these distal schizophrenia GWAS loci regulates FOXG1 expression, supporting its potential role as a schizophrenia risk gene. This work provides a framework for understanding the effect of non-coding regulatory elements on human brain development and the evolution of cognition, and highlights novel mechanisms underlying neuropsychiatric disorders.
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Gene Expression Omnibus
Sequencing data from this study have been deposited in the Gene Expression Omnibus and dbGaP under the accession number GSE77565 and phs001190.v1.p1, respectively.
This work is a component of the psychENCODE project and was supported by NIH grants to D.H.G. (5R01MH060233; 5R01MH100027; 3U01MH103339; 1R01MH110927; 1R01MH094714), F.H. and E.E. (R01MH101782; R01ES022282; T32MH073526), J.L.S. (K99MH102357), and J.E. (R01ES024995), NSF CAREER Award (#1254200) to J.E., Glenn/AFAR Postdoctoral Fellowship Program (20145357) and Basic Science Research Program through the National Research Foundation of Korea (2013024227) to H.W., CIRM- BSCRC Training Grant (TG2-01169) to L.T.U., NRSA Training Grant to N.N.P. (F30MH099886; UCLA MSTP), NHMRC project grant (APP1062510) and ARC DECRA fellowship (DE140101033) to I.V. The Hi-C library was sequenced by the BSCRC, and fetal tissue was collected from the UCLA Center for Aids Research (CFAR, 5P30 AI028697). Schizophrenia RNA-seq data were generated as part of the CommonMind Consortium (see Methods and Supplementary Information). eQTL data was provided by M. Ryten and A. Ramasamy. We thank S. Feng, Y. Tian, V. Swarup, and P. S. Mischel for helpful discussions and critical reading of the manuscript.
Extended data figures
This file contains Supplementary Tables 1-27.
About this article
Current Opinion in Neurobiology (2019)