精神疾患患者におけるセロトニントランスポーター遺伝子のエピゲノム変化と低活性遺伝子型の関連解析

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 戸田 達史, 東京大学教授 徳永 勝士, 東京大学教授 狩野 方伸, 東京大学准教授 金生 由紀子, 東京大学講師 岩田 淳University of Tokyo(東京大学

CNVs in Three Psychiatric Disorders

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD

Use of human methylation arrays for epigenome research in the common marmoset (Callithrix jacchus)

tWe examined the usefulness of commercially available DNA methylation arrays designed for the humangenome (Illumina HumanMethylation450 and MethylationEPIC) for high-throughput epigenome analysisof the common marmoset, a nonhuman primate suitable for research on neuropsychiatric disorders. Fromamong the probes on the methylation arrays, we selected those available for the common marmoset. DNAmethylation data were obtained from genomic DNA extracted from the frontal cortex and blood samplesof adult common marmosets as well as the frontal cortex of neonatal marmosets. About 10% of the probeson the arrays were estimated to be useful for DNA methylation assay in the common marmoset. Strongcorrelations existed between human and marmoset DNA methylation data. Illumina methylation arraysare useful for epigenome research using the common marmoset

Population-neuroscience study of the Tokyo TEEN Cohort (pn-TTC):Cohort longitudinal study to explore the neurobiological substrates of adolescent psychological and behavioral development.

Adolescence is a crucial stage of psychological development and is critically vulnerable to the onset of psychopathology. However, our understanding of how maturation of endocrine, epigenetics, and brain circuit may underlie the psychological development in adolescence has not been integrated. Here, we introduce our research project, the "population-neuroscience study of the Tokyo TEEN Cohort (pn-TTC)," a longitudinal study to explore the neurobiological substrates of development during adolescence

Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights

Summary: Compelling evidence in Caucasian populations suggests a role for copy-number variations (CNVs) in autism spectrum disorder (ASD) and schizophrenia (SCZ). We analyzed 1,108 ASD cases, 2,458 SCZ cases, and 2,095 controls in a Japanese population and confirmed an increased burden of rare exonic CNVs in both disorders. Clinically significant (or pathogenic) CNVs, including those at 29 loci common to both disorders, were found in about 8% of ASD and SCZ cases, which was significantly higher than in controls. Phenotypic analysis revealed an association between clinically significant CNVs and intellectual disability. Gene set analysis showed significant overlap of biological pathways in both disorders including oxidative stress response, lipid metabolism/modification, and genomic integrity. Finally, based on bioinformatics analysis, we identified multiple disease-relevant genes in eight well-known ASD/SCZ-associated CNV loci (e.g., 22q11.2, 3q29). Our findings suggest an etiological overlap of ASD and SCZ and provide biological insights into these disorders. : Kushima et al. perform comparative analyses of CNVs in ASD and SCZ in a Japanese population. They identify pathogenic CNVs and biological pathways in each disorder with significant overlap. Patients with pathogenic CNVs have a higher prevalence of intellectual disability. Disease-relevant genes are detected in eight well-known ASD/SCZ-associated CNV loci. Keywords: autism spectrum disorder, schizophrenia, copy-number variation, array comparative genomic hybridization, genetic overlap, Japanese population, oxidative stress response, genome integrity, lipid metabolism, gene ontolog