Many psychiatric disorders are considered highly heritable, based on family or twin studies. Since their clinical diagnosis relies on interviews, each psychiatric disorder consists of a genetically and symptomatically heterogeneous population. To homogenize the disorder, we genetically analyzed patients with distinctive phenotypes encountered at the bedside. In this report, I present genetic analyses that were performed on a family with bipolar disorder that responded well to lithium carbonate and a family with schizophrenia and minor malformations and intellectual disability. Although each group consisted of only one family, we were able to successfully identify candidate disease mutations using the positional cloning method. The mutations were very rare and were predicted to strongly influence the onset of bipolar disorder and schizophrenia, respectively, from the onset. However, further functional analysis is required to confirm the implication of these gene products in the molecular pathology of these diseases.

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Despite advances in the treatment of schizophrenia, there are still limitations, and we have wondered if clarifying the pathophysiology of schizophrenia might help solve such problems. We are investigating the biological pathogenesis of schizophrenia by following phenomena that may be related to the pathophysiology of schizophrenia. Here, we present our attempts using chromosomal translocations and the side effects of antipsychotic drugs as clues.

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Rare risk variants for schizophrenia with a large effect size have been progressively identified mainly in European populations. We showed that novel SETD1A missense variants were exclusively identified in Japanese patients with schizophrenia and that a rare UNC13B missense variant segregated with schizophrenia in a multiplex family with 10 affected individuals. Further studies should be performed to discover rare risk variants for schizophrenia, including structural variants and somatic de novo mutations, in diverse populations.

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Many things in the world have exceptions. For example, the genome sequence of each cell in the human body is not always the same. This is because there are somatic mutations, changes in the genome sequence that are generated in some cells during their differentiation and growth. Somatic mutations are known to cause human diseases such as cancer and focal cortical dysplasia. Also there is accumulating evidence supporting the contribution of somatic mutations to the pathogenesis of neuropsychiatric disorders. In this review, I will introduce our own research showing that deleterious somatic mutations in genes known to be causal for neurodevelopmental disorders, which affect some but not all cells, may confer the risk of bipolar disorder. Subsequently, recent findings from comprehensive genetic explorations of the association between somatic mutations and neuropsychiatric disorders using peripheral or brain tissue samples will be overviewed.

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Recent advances in genome analysis have revealed that somatic mosaicism, a specific condition of clonal hematopoiesis, increases with age and confers a risk of hematological malignancy in healthy individuals. Recent studies have demonstrated that somatic mutations occur in the normal brain neurons by different mechanisms and at different rates during development through ageing. Some mutations in normal brain were found to be involved in clonal hematopoiesis, such as DNMT3A. This result suggests that somatic mosaicism in neurons accumulate with age. Somatic mosaicism, from point mutations to large‐scale chromosomal alteration, are thought to be enriched in blood or neurons of neurodevelopmental diseases like autism spectrum disorder and schizophrenia, and may are related to the development of neurodevelopmental diseases. Here, we will present the somatic mosaicism in normal neurons and relationships between somatic mosaicism and neurodevelopment diseases.

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Somatic mutations are a kind of genomic variants that occur during the developmental stages after fertilization and exist in a mosaic‐like pattern in individuals. Some of the brain‐specific somatic mutations have been reported to cause neurological diseases. We have especially focused on long interspersed nuclear element‐1 (LINE‐1) insertions, a type of retrotransposon, and have found that the LINE‐1 copy number was increased in neurons of schizophrenia patients and that the newly inserted LINE‐1 were located near the genes involved in neuronal functions. To identify the detailed profiles of the LINE‐1 insertion genomic sites, we established a new single‐cell‐level analysis method, NECO‐seq, and performed a case‐control analysis using the postmortem brains of schizophrenia patients. Analysis of a total of more than 1,000 neuronal nuclei showed that LINE‐1 insertions that occurred at a relatively early stage in neurogenesis accumulated near the neuron‐related genes, including neurotransmitter receptors. These LINE‐1 insertions may have a profound effect on neuronal morphology and function.

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In recent years, genome‐editing technology has made it possible to modify the target genome sequences of a wide variety of cells and organisms. However, the conventional homology‐directed repair‐mediated editing method can only be applied to rapidly dividing cells because it uses a cell cycle‐dependent DNA repair mechanism. Therefore, it has been difficult to modify the target genes in somatic cells that are in a non‐dividing state. To overcome this limitation, we have developed robust strategies, Homology‐Independent Targeted Integration (HITI) and intercellular linearized Single homology Arm donor‐mediated intron‐Targeting Integration (SATI) , which enable efficient targeted gene knock‐in in non‐dividing cells, both in vitro and in vivo. Here, I will introduce the technologies of somatic gene manipulation using HITI and SATI.

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Since the multi‐site properly‐harmonized datasets in human brain magnetic resonance imaging (MRI) have been available, the machine learning classifiers to predict clinical diagnoses and prognosis and the biological reclassification in psychiatric disorders will be used in clinical practice soon. When these new research paradigms become more common, hierarchical dataset combining with genetic information, etc., will be important for elucidating the pathophysiology and developing clinically applicable tools in multiple psychiatric disorders. There are several reasons why brain imaging research on psychiatric disorders should be promoted in Japan, especially, one reason is that psychiatrists are deeply involved in the research. The development of biological tools collaborating with clinicians and patients is important in the phase of clinical application. In terms of understanding pathophysiology, brain imaging data across the life course from childhood to old age, especially during adolescence, combing with hierarchical database is expected to be utilized. As these datasets continue to expand in both quality and quantity, psychiatrists will become limited roles in the whole research projects. However, the psychiatrists need to organize cross‐disciplinary teams to lead to an appropriate form of the clinical research in psychiatry.

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