The authors identified DMRs (differentially methylated regions) in neurons and non-neurons by DNA methylation analysis using MBD2B in frontal lobe samples of patients with bipolar disorder. In both cell types, the promoter region showed global hypomethylation, and gene-specific hypermethylation was observed in neurons. The background of gene-specific hypermethylation was considered to be the increased expression of DNMT3B. We also showed that mood stabilizers showed methylation changes in the opposite direction to the postmortem brain, and that DMRs were significantly accumulated in the GWAS region of bipolar disorder.

View full abstract

In advancing epidemiological study, the improvement of both cohort study and biobank is essential. Also, the development of statistical genetics approaches to identify disease risk factors is indispensable. In this article, we will review the recent biobank and cohort study to promote epidemiological research, and introduce the Tohoku Medical Megabank Project, which includes the largest three‐generation birth cohort in the world. Next, we describe the “missing heritability”, which is one of the most difficult issue in cohort research, and show one of the hypotheses, the polygenic model, to overcome this. In addition, we introduce the iWate PolyGenic Model (iPGM) based on the polygenic model to predict genetic predisposition to Ischemic stroke. Finally, we discuss effective approaches toward prediction of multifunctional disorders such as psychiatric disorders through cohort study.

View full abstract

Global multiethnic genome‐wide association studies have elucidated the genetic factors of diseases that affect humans and the influence of ethnicity on the association of each gene polymorphism or variation with psychiatric and other diseases. Therefore, to actualize personalized medicine in Japan, the activities of biobanks that collect biospecimens and data from Japanese people are crucial. The Tohoku Medical Megabank Project biobank, which has collected biospecimens and data from 150,000 participants in population cohort studies, as well as Biobank Japan and the National Center Biobank Network, both of which have collected biospecimens and data from patients, are the representative biobanks in Japan. Biospecimens (i. e., DNA, plasma, serum, urine, and blood cells) and data (i. e., cohort data, clinical data, and genomics data) in biobanks have been used in multiple studies, such as genomics, gene function, biomarker, pharmacogenomics, immunity, and stress response studies, for the actualization of personalized medicine.

View full abstract

For complex diseases, including psychiatric disorders, genetic and environmental risk factors were investigated using genomic and epidemiological methods. However, genomics is faced by the so‐called “missing heritability” problem, and epidemiology is limited by the reproducibility crisis for small effect risk factors. A research design called prospective genome cohort is expected to overcome these limitations. Prospective genomic cohorts collect genomic and environmental exposure information for a defined population and store biological samples such as blood and urine under a controlled quality. Besides, genome cohorts prospectively obtain disease onset information and various endophenotypes such as laboratory tests, brain imaging, and questionnaire survey. With the prospective genome cohort, new risk factors, including gene‐environment interactions, will be identified. However, genome cohort studies have unique difficulties. One is the p >> n problem, and the other is the problem in extracting meaningful features from diverse and multi‐layered endophenotypic information. Here, we will present examples of statistical machine learning and deep learning techniques that are expected to address these problems.

View full abstract

Progress in genomic medicine has provided novel insight of susceptibility genes for complex disorders, including psychiatric disorders. These results revealed the fact that the effect size of the “associated” single nucleotide polymorphisms (SNPs) is small, as well as that the variants with large effect size are rare. This indicates that a very large number of subjects will be required to detect significant SNPs or variants. Taken these into account, the author reviewed the recent findings of psychiatric genomics and introduced the importance of collaborative effort for generating the large “sample size” or “secondary use” of biobank resources (data from genome‐wide association studies, whole exome/genome sequencing analysis) , aiming to establish the personalized medicine. COI : No potential conflicts of interest were disclosed

View full abstract

Patients with mental illnesses and their families have strong expectations for psychiatric research to find a curative treatment. Nevertheless, diagnosis and treatment methods based on the pathogenesis of mental disorders have yet to be found. Starting from genome analysis research, there is a strong need to identify phenotypes and functional abnormalities that occur at the molecular, cellular, neural circuit, brain, and individual levels of the disease, to comprehensively clarify the pathogenesis, and to develop pathology‐based diagnostics and fundamental therapeutic drug, and knowledge is being accumulated. In order to promote further development, it is essential to establish a patient‐derived bioresource infrastructure with clinical information in order to aggregate genomic information across multiple institutions, departments, and diseases. In Japan, the establishment of integrated center for neurology and psychiatry genomics (iCNPG) is required as an organization to promote the enhancement of medical care and research for neuropsychiatric disorders while adhering to various ethical guidelines, with the aim of (1) consolidating information to take advantage of scale, (2) implementing data science, (3) promoting data sharing, and (4) achieving sustainability.

View full abstract

Technologies for personalized medicine, which enables decision‐making for effective and safe medical practice adjusted for each individual based on genome and other biological information, have been developed and installed in various medical fields, such as cancer medicine. In 2012, the following year of the Great East Japan Earthquake, the Tohoku Medical Megabank Project was founded as a flagship project for rebuilding the medical system in the devastated region and as a core resource to develop a personalized medicine system of the nation. The cohort (consists of 150,000 residents) has investigated health, lifestyle, and environmental information, provided feedback and support to the communities and accumulated genome and other biological information. The project targets a wide range of health problems, including psychiatric conditions such as depression. It is expected that the project contributes to the elucidation of the pathogeneses of neuropsychiatric disorders and the development of personalized psychiatric medicine.

View full abstract

Immune responses often play an important role in the pathogenesis of neuropsychiatric disorders. T‐helper 17 (Th17) cells are a subset of CD4⁺ T cells that produce interleukin (IL) ‐17A. Recent studies showed that an increase in circulating IL‐17A causes cognitive dysfunction, although it is unknown how increased systemic IL‐17A affects brain function. Using transgenic mice overexpressing RORγt, a transcription factor essential for differentiation of Th17 cells (RORγt Tg mice) , we examined changes in the brain caused by chronically increased IL‐17A resulting from excessive activation of Th17 cells. RORγt Tg mice exhibited upregulated Rorc and Il17A mRNA expression in the colon, as well as a constitutive increase in circulating IL‐17A. We found that the immunoreactivity of Iba1 and density of Iba1+ microglia were lower in the dentate gyrus of RORγt Tg mice compared with wild‐type mice. However, GFAP⁺ astrocytes were unchanged in the hippocampi of RORγt Tg mice. In addition, novel object location test results indicated no difference in preference between these mice. Our findings indicate that a continuous increase of IL‐17A in response to RORγt overexpression resulted in decreased microglia activity in the dentate gyrus.

View full abstract