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The molecular pathology of schizophrenia: an overview of existing knowledge and new directions for future research

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MOLECULAR PSYCHIATRY
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DOI: 10.1038/s41380-023-02005-2

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Despite ongoing efforts to understand the molecular pathology of schizophrenia, it remains elusive. However, in the past two decades, significant progress has been made in understanding the genetic pathology, with over 20% of the liability to schizophrenia explained by common genetic variants. Rare mutations in specific genes have also been identified to substantially increase the risk for schizophrenia. These findings, along with studies on brain models and patient tissues, have provided new insights into the molecular pathology of schizophrenia.
Despite enormous efforts employing various approaches, the molecular pathology in the schizophrenia brain remains elusive. On the other hand, the knowledge of the association between the disease risk and changes in the DNA sequences, in other words, our understanding of the genetic pathology of schizophrenia, has dramatically improved over the past two decades. As the consequence, now we can explain more than 20% of the liability to schizophrenia by considering all analyzable common genetic variants including those with weak or no statistically significant association. Also, a large-scale exome sequencing study identified single genes whose rare mutations substantially increase the risk for schizophrenia, of which six genes (SETD1A, CUL1, XPO7, GRIA3, GRIN2A, and RB1CC1) showed odds ratios larger than ten. Based on these findings together with the preceding discovery of copy number variants (CNVs) with similarly large effect sizes, multiple disease models with high etiological validity have been generated and analyzed. Studies of the brains of these models, as well as transcriptomic and epigenomic analyses of patient postmortem tissues, have provided new insights into the molecular pathology of schizophrenia. In this review, we overview the current knowledge acquired from these studies, their limitations, and directions for future research that may redefine schizophrenia based on biological alterations in the responsible organ rather than operationalized criteria.

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