39Whereas highly penetrant variants have proven well-suited to human induced
62. CC-BY-NC-ND 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. 4,5,19 ; the ability of an hiPSC-based 75 approach to resolve the much smaller effects of common variants remained 76 uncertain.
78We established a case-control SZ cohort structure designed to capture a broad (Fig. 1). Because hiPSC-83 neurons are likely best suited for the study of disease predisposition 13,[21][22][23][24] , we 84 applied this methodology to a childhood-onset SZ (COS) cohort, a subset of SZ 85 patients defined by onset, severity and prognosis [25][26][27] . COS patients have a comprised of nearly equal numbers of cases and controls (Fig. 1A,B,C)
To explore modular organization of chromosomes in schizophrenia (SCZ) and bipolar disorder (BD), we applied 'population-scale' correlational structuring of 739 histone H3-lysine 27 acetylation and H3-lysine 4 trimethylation profiles, generated from the prefrontal cortex (PFC) of 568 cases and controls. Neuronal histone acetylomes and methylomes assembled as thousands of cis-regulatory domains (CRDs), revealing fine-grained, kilo- to megabase scale chromatin organization at higher resolution but firmly integrated into Hi-C chromosomal conformations. Large clusters of domains that were hyperacetylated in disease shared spatial positioning within the nucleus, predominantly regulating PFC projection neuron function and excitatory neurotransmission. Hypoacetylated domains were linked to inhibitory interneuron- and myelination-relevant genes. Chromosomal modular architecture is affected in SCZ and BD, with hyperacetylated domains showing unexpectedly strong convergences defined by cell type, nuclear topography, genetic risk, and active chromatin state across a wide developmental window.
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