Psychiatric disorders such as schizophrenia and bipolar disorder are caused by complex gene-environment interactions. While recent advances in genomic technologies have enabled the identification of ...several risk variants for psychiatric conditions, including single-nucleotide variants and copy-number variations, these factors can explain only a portion of the liability to these disorders. Although non-inherited factors had previously been attributed to environmental causes, recent genomic analyses have demonstrated that de novo mutations are among the main non-inherited risk factors for several psychiatric conditions. Somatic mutations in the brain may also explain how stochastic developmental events and environmental insults confer risk for a psychiatric disorder following fertilization. Here, we review evidence regarding somatic mutations in the brains of individuals with and without neuropsychiatric diseases. We further discuss the potential biological mechanisms underlying somatic mutations in the brain as well as the technical issues associated with the detection of somatic mutations in psychiatric research.
Psychiatric disorders such as bipolar disorder and schizophrenia are highly heritable. While the genetic contribution to psychiatric disorders is quite sure, specific genetic factors contributing to ...particular conditions have long been a mystery. Empowered by the initial report of the Human Genome Project, the analysis of the comprehensive set of the human genome, called “genomics,” became possible. Subsequent development of large-scale genomic technologies enabled us to elucidate various disease-related genetic information, accelerating our understanding of various diseases. Genomic research on psychiatric disorders is not an exception. In this Review, I introduce significant advancements in psychiatric genomics with a special focus on our investigation of bipolar disorder. International consortiums and advocacy groups accelerate psychiatric genomics, increasing the sample size and statistical power for robust findings. The genetic architecture of schizophrenia has been elucidated in both common and rare variant studies. The genetic architecture of autism spectrum disorder (ASD) has been elucidated mainly by rare variant analysis. As to bipolar disorder, common variant analysis precedes rare variant analysis, but we are struggling to elucidate relevant rare variants. While the genomic approach has explained specific genetic factors for particular disorders, overlapping risk genes or pleiotropy has been observed more than expected. The boundary in the current nosology of psychiatric disorders is more or less challenged. To understand the genotype-phenotype relation more deeply, an attempt to understand phenotypes based on genotypes, called the “genotype first” approach, has started. I discuss this new approach for better understanding and treatment of psychiatric disorders.
Epidemiological studies have revealed that schizophrenia is highly heritable. However, genetic studies have not fully elucidated its etiology. Accumulating evidence suggests that epigenetic ...alterations may provide an additional explanation of its pathophysiology. We investigated the methylation profiles of DNA in peripheral blood cells from 18 patients with first-episode schizophrenia (FESZ) and from 15 normal controls. Schizophrenia patients were confined to those at the stage of first-episode psychosis. We analyzed the DNA methylation status of 27,578 CpG sites by means of the Illumina Infinium HumanMethylation27 BeadChip array. Differentially methylated CpG sites, which were particularly abundant within CpG islands, were enriched in genes related to the nuclear lumen, to transcription factor binding, and to nucleotide binding. We also observed differential methylation of the promoters of HTR1E and COMTD1, which are functionally related to genes found to be differentially methylated in schizophrenia patients in previous studies. Our results indicate the site-specific epigenetic alterations in patients with FESZ.
Abstract
Bipolar disorder is a severe mental illness characterized by recurrent manic and depressive episodes. To better understand its genetic architecture, we analyze ultra-rare de novo mutations ...in 354 trios with bipolar disorder. For germline de novo mutations, we find significant enrichment of loss-of-function mutations in constrained genes (corrected-
P
= 0.0410) and deleterious mutations in presynaptic active zone genes (FDR = 0.0415). An analysis integrating single-cell RNA-sequencing data identifies a subset of excitatory neurons preferentially expressing the genes hit by deleterious mutations, which are also characterized by high expression of developmental disorder genes. In the analysis of postzygotic mutations, we observe significant enrichment of deleterious ones in developmental disorder genes (
P
= 0.00135), including the
SRCAP
gene mutated in two unrelated probands. These data collectively indicate the contributions of both germline and postzygotic mutations to the risk of bipolar disorder, supporting the hypothesis that postzygotic mutations of developmental disorder genes may contribute to bipolar disorder.
Schizophrenia is a severe psychiatric disease affecting about 1% of the world's population, with significant effects on patients and society. Genetic studies have identified several candidate risk ...genes or genomic regions for schizophrenia, and epidemiological studies have revealed several environmental risk factors. However, the etiology of schizophrenia still remains largely unknown. Epigenetic mechanisms such as DNA methylation and histone modifications can explain the interaction between genetic and environmental factors at the molecular level, and accumulating evidence suggests that such epigenetic alterations are involved in the pathophysiology of schizophrenia. However, replication studies to validate previous findings and investigations of the causality of epigenetic alterations in schizophrenia are needed. Here, we review epigenetic studies of schizophrenia patients using postmortem brains or peripheral tissues, focusing mainly on DNA methylation. We also highlight the recent progress and challenges in characterizing the potentially complex and dynamic patterns of epigenomic variations. Such studies are expected to contribute to our understanding of schizophrenia etiology and should provide novel opportunities for the development of therapeutic drugs.
This paper proposes a data-assimilated lifecycle simulation (DA-LCS) system. Data assimilation (DA) is a self-adjustment method for decreasing differences between a simulation and observation data ...from an actual-system by conforming the simulation model parameters to the observation at appropriate time intervals. The proposed system applies DA to LCS for adaptive operations in product lifecycle management. A case study of the lifecycle of a photovoltaic panel reuse business shows that DA-LCS successfully merges measurement data acquired from actual business operations into the LCS model, and sequentially revises the simulation estimations through DA.
Multichannel near-infrared spectroscopy (NIRS) is a functional neuroimaging modality that enables easy-to-use and noninvasive measurement of changes in blood oxygenation levels. We developed a ...clinically-applicable method for estimating resting state functional connectivity (RSFC) with NIRS using a partial correlation analysis to reduce the influence of extraneural components. Using a multi-distance probe arrangement NIRS, we measured resting state brain activity for 8min in 17 healthy participants. Independent component analysis was used to extract shallow and deep signals from the original NIRS data. Pearson's correlation calculated from original signals was significantly higher than that calculated from deep signals, while partial correlation calculated from original signals was comparable to that calculated from deep (cerebral-tissue) signals alone. To further test the validity of our method, we also measured 8min of resting state brain activity using a whole-head NIRS arrangement consisting of 17 cortical regions in 80 healthy participants. Significant RSFC between neighboring, interhemispheric homologous, and some distant ipsilateral brain region pairs was revealed. Additionally, females exhibited higher RSFC between interhemispheric occipital region-pairs, in addition to higher connectivity between some ipsilateral pairs in the left hemisphere, when compared to males. The combined results of the two component experiments indicate that partial correlation analysis is effective in reducing the influence of extracerebral signals, and that NIRS is able to detect well-described resting state networks and sex-related differences in RSFC.
Background
Rubinstein–Taybi syndrome (RTS) is a rare autosomal‐dominant disease. Almost all cases are sporadic and attributed to de novo variant. Psychotic symptoms in RTS are rare and have been ...reported in only a few published cases. On the other hand, 22q11.2 deletion syndrome is the most common chromosomal microdeletion in humans. The 22q11.2 deletion is well recognized as a risk factor for schizophrenia. Here, we present a schizophrenic psychosis case clinically diagnosed as RTS but resolved as carrying 22q11.2 deletion by genomic analysis.
Case presentation
A 38‐year‐old Japanese male was admitted to our hospital due to psychotic symptoms. He had been diagnosed with RTS based on physical characteristics at the age of 9 months. On admission, we performed whole exome sequencing. He had no pathogenic variant in CREBBP or EP300. We detected 2.5 Mb deletion on 22q11.2 and one rare loss‐of‐function variant in a loss‐of‐function‐constrained gene (MTSS1) and three rare missense variants in missense‐constrained genes (CELSR3, HERC1, and TLN1). Psychotic symptoms were ameliorated by the treatment of risperidone.
Conclusion
The psychiatric manifestation and genomic analysis may be a clue to detecting 22q11.2 deletion syndrome in undiagnosed patients. The reason for similarity in physical characteristics in 22q11.2 deletion syndrome and RTS remains unresolved. The 22q11.2 deletion and HERC1 contribute to the patient's phenotype.
Venn diagram for explanation of the overlap phenotypes.
Aim
Hypofunction of N‐methyl‐D‐aspartate receptors (NMDAR) may contribute to the pathophysiology of schizophrenia (SCZ). Recently, the glycine cleavage system (GCS) was shown to affect NMDAR function ...in the brain. GCS functional defects cause nonketotic hyperglycinemia, the atypical phenotype of which presents psychiatric symptoms similar to SCZ. Here, we examined the involvement of GCS in SCZ.
Methods
First, to identify the rare variants and the exonic deletions, we resequenced all the coding exons and the splice sites of four GCS genes (GLDC, AMT, GCSH, and DLD) in 474 patients with SCZ and 475 controls and performed multiplex ligation‐dependent probe amplification analysis in SCZ. Next, we performed metabolome analysis using plasma of patients harboring GCS variants (n = 5) and controls (n = 5) by capillary electrophoresis time‐of‐flight mass spectrometry. The correlation between plasma metabolites and Positive and Negative Syndrome Scale score was further examined.
Results
Possibly damaging variants were observed in SCZ: A203V, S801N in GLDC, near the atypical nonketotic hyperglycinemia causative mutations (A202V, A802V); G825D in GLDC, a potential neural tube defect causative mutation; and R253X in AMT. Marked elevation of plasma 5‐oxoproline (pyroglutamic acid), aspartate, and glutamate, which might affect NMDAR function, was observed in patients harboring GCS variants. The aspartate level inversely correlated with negative symptoms (r = −0.942, P = 0.0166).
Conclusion
These results suggest that GCS rare variants possibly contribute to the pathophysiology of SCZ by affecting the negative symptoms through elevation of aspartate.
Adrenal Ewing's Sarcoma in an Elderly Man Toda, Kazuyoshi; Ishii, Sumiyasu; Yasuoka, Hidetoshi ...
Internal Medicine,
01/2018, Letnik:
57, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Ewing's sarcoma usually arises in the bones of children and adolescents. We herein report a 74-year-old man with Ewing's sarcoma in the adrenal gland. The diagnosis was confirmed by a genetic test, ...pathological studies, and several imaging studies. He already had multiple liver metastases when he was transferred to our hospital and died on the 37th day. The diagnosis was further confirmed by autopsy studies. Adrenal Ewing's sarcoma is very rare, and our patient was older than other reported cases. Ewing's sarcoma should be considered even in elderly patients with adrenal tumors.
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