The three-dimensional landscape of the genome in human brain tissue unveils regulatory mechanisms leading to schizophrenia risk

Recent advances in our understanding of the genetic architecture of schizophrenia have shed light on the schizophrenia etiology. While common variation is one of the major genetic contributors, the majority of common variation reside in non-coding genome, posing a significant challenge in understanding the functional impact of this class of genetic variation. Functional genomic datasets that range from expression quantitative trait loci (eQTL) to chromatin interactions are critical to identify the potential target genes and functional consequences of non-coding variation. In this review, we discuss how three-dimensional chromatin landscape, identified by a technique called Hi-C, has facilitated the identification of potential target genes impacting schizophrenia risk. We outline key steps for Hi-C driven gene mapping, and compare Hi-C defined schizophrenia risk genes defined across developmental epochs and cell types, which offer rich insights into the temporal window and cellular etiology of schizophrenia. In contrast with a neurodevelopmental hypothesis in schizophrenia, Hi-C defined schizophrenia risk genes are postnatally enriched, suggesting that postnatal development is also important for schizophrenia pathogenesis. Moreover, Hi-C defined schizophrenia risk genes are highly expressed in excitatory neurons, highlighting excitatory neurons as a central cell type for schizophrenia. Further characterization of Hi-C defined schizophrenia risk genes demonstrated enrichment for genes that harbor loss-of-function variation in neurodevelopmental disorders, suggesting a shared genetic etiology between schizophrenia and neurodevelopmental disorders. Collectively, moving the search space from risk variants to the target genes lays a foundation to understand the neurobiological basis of schizophrenia.