To explore the developmental reorganization of the three-dimensional genome of the brain in the context of neuropsychiatric disease, we monitored chromosomal conformations in differentiating neural progenitor cells. Neuronal and glial differentiation was associated with widespread developmental remodeling of the chromosomal contact map and included interactions anchored in common variant sequences that confer heritable risk for schizophrenia. We describe cell type–specific chromosomal connectomes composed of schizophrenia risk variants and their distal targets, which altogether show enrichment for genes that regulate neuronal connectivity and chromatin remodeling, and evidence for coordinated transcriptional regulation and proteomic interaction of the participating genes. Developmentally regulated chromosomal conformation changes at schizophrenia-relevant sequences disproportionally occurred in neurons, highlighting the existence of cell type–specific disease risk vulnerabilities in spatial genome organization.

The mechanisms by which common risk variants of small effect interact to contribute to complex genetic disorders remain unclear. Here, we apply a genetic approach, using isogenic human induced pluripotent stem cells (hiPSCs), to evaluate the effects of schizophrenia-associated common variants predicted to function as brain expression quantitative trait loci (SZ-eQTLs). By integrating CRISPR-mediated gene editing, activation and repression technologies to study one putative SZ-eQTL (FURIN rs4702) and four top-ranked SZ-eQTL genes (FURIN, SNAP91, TSNARE1, CLCN3), our platform resolves pre-and post-synaptic neuronal deficits, recapitulates genotype-dependent gene expression differences, and identifies convergence downstream of SZ-eQTL gene perturbations. Our observations highlight the cell-type-specific effects of common variants and demonstrate a synergistic effect between SZ-eQTL genes that converges on synaptic function. We propose that the links between rare and common variants implicated in psychiatric disease risk constitute a potentially generalizable phenomenon occurring more widely in complex genetic disorders.

We report locus-specific disintegration of megabase-scale chromosomal conformations in brain after neuronal ablation of Kmt1e/Setdb1 histone H3-lysine 9 methyltransferase, including a large topologically associated 1.2Mb domain conserved in human and mouse and encompassing >70 genes at the clustered Protocadherin (cPcdh) locus. TADcPcdh in mutant neurons showed abnormal accumulations of CTCF transcriptional regulator and 3D genome organizer at cryptic binding sites, converted into permissive state with DNA cytosine hypomethylation and histone hyperacetylation. Broadly upregulated expression across cPcdh included defective S-type Protocadherin single-cell stochastic constraint. Setdb1-dependent loop formations, bypassing 0.2–1Mb of linear genome, radiated from TADPcdh fringes towards cPcdh cis-regulatory sequences, counterbalanced shorter-range facilitative promoter-enhancer contacts and carried loop-bound polymorphisms associated with genetic risk for schizophrenia. We show that KRAB-zinc finger Setdb1 repressor complex, shielding neuronal 3D genomes from excess CTCF binding, is critically required for structural maintenance of TADcPcdh.