Tadafumi Kato

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Organization: RIKEN Brain Science Institute , Japan

Department: Laboratory for Molecular Dynamics of Mental Disorders

Title: (PhD)

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References

Neurobiological basis of bipolar disorder: Mitochondrial dysfunction hypothesis and beyond

Co-reporter:Tadafumi Kato

Schizophrenia Research 2017 Volume 187(Volume 187) pp:

Publication Date(Web):1 September 2017

DOI:10.1016/j.schres.2016.10.037

Bipolar disorder is one of two major psychotic disorders together with schizophrenia and causes severe psychosocial disturbance. Lack of adequate animal models hampers development of new mood stabilizers. We proposed a mitochondrial dysfunction hypothesis and have been studying the neurobiology of bipolar disorder based on this hypothesis. We showed that deletions of mitochondrial DNA (ΔmtDNA) play a pathophysiological role at least in some patients with bipolar disorder possibly by affecting intracellular calcium regulation. Mutant polymerase γ transgenic mice that accumulate ΔmtDNA in the brain showed recurrent spontaneous depression-like episodes which were prevented by a serotonin-selective reuptake inhibitor and worsened by lithium withdrawal. The animal model would be useful to develop new mood stabilizers.

Exome sequencing for bipolar disorder points to roles of de novo loss-of-function and protein-altering mutations

Co-reporter:M Kataoka, N Matoba, T Sawada, A-A Kazuno, M Ishiwata, K Fujii, K Matsuo, A Takata and T Kato

Molecular Psychiatry 2016 21(7) pp:885-893

Publication Date(Web):May 24, 2016

DOI:10.1038/mp.2016.69

Although numerous genetic studies have been conducted for bipolar disorder (BD), its genetic architecture remains elusive. Here we perform, to the best of our knowledge, the first trio-based exome sequencing study for BD to investigate potential roles of de novo mutations in the disease etiology. We identified 71 de novo point mutations and one de novo copy-number mutation in 79 BD probands. Among the genes hit by de novo loss-of-function (LOF; nonsense, splice site or frameshift) or protein-altering (LOF, missense and inframe indel) mutations, we found significant enrichment of genes highly intolerant (first percentile of intolerant genes assessed by Residual Variation Intolerance Score) to protein-altering variants in general population, an observation that is also reported in autism and schizophrenia. When we performed a joint analysis using the data of schizoaffective disorder in published studies, we found global enrichment of de novo LOF and protein-altering mutations in the combined group of bipolar I and schizoaffective disorders. Considering relationship between de novo mutations and clinical phenotypes, we observed significantly earlier disease onset among the BD probands with de novo protein-altering mutations when compared with non-carriers. Gene ontology enrichment analysis of genes hit by de novo protein-altering mutations in bipolar I and schizoaffective disorders did not identify any significant enrichment. These results of exploratory analyses collectively point to the roles of de novo LOF and protein-altering mutations in the etiology of bipolar disorder and warrant further large-scale studies.

Depression-like episodes in mice harboring mtDNA deletions in paraventricular thalamus

Co-reporter:T Kasahara, A Takata, T M Kato, M Kubota-Sakashita, T Sawada, A Kakita, H Mizukami, D Kaneda, K Ozawa and T Kato

Molecular Psychiatry 2016 21(1) pp:39-48

Publication Date(Web):October 20, 2015

DOI:10.1038/mp.2015.156

Depression is a common debilitating human disease whose etiology has defied decades of research. A critical bottleneck is the difficulty in modeling depressive episodes in animals. Here, we show that a transgenic mouse with chronic forebrain expression of a dominant negative mutant of Polg1, a mitochondrial DNA (mtDNA) polymerase, exhibits lethargic behavioral changes, which are associated with emotional, vegetative and psychomotor disturbances, and response to antidepression drug treatment. The results suggested a symptomatic similarity between the lethargic behavioral change that was recurrently and spontaneously experienced by the mutant mice and major depressive episode as defined by DSM-5. A comprehensive screen of mutant brain revealed a hotspot for mtDNA deletions and mitochondrial dysfunction in the paraventricular thalamic nucleus (PVT) with similar defects observed in postmortem brains of patients with mitochondrial disease with mood symptoms. Remarkably, the genetic inhibition of PVT synaptic output by Cre-loxP-dependent expression of tetanus toxin triggered de novo depression-like episodes. These findings identify a novel preclinical mouse model and brain area for major depressive episodes with mitochondrial dysfunction as its cellular mechanism.

Hypermethylation of serotonin transporter gene in bipolar disorder detected by epigenome analysis of discordant monozygotic twins

Co-reporter:H Sugawara, K Iwamoto, M Bundo, J Ueda, T Miyauchi, A Komori, A Kazuno, N Adati, I Kusumi, Y Okazaki, J Ishigooka, T Kojima and T Kato

Translational Psychiatry 2011 Volume 1(Jul) pp:e24

Publication Date(Web):2011-07-01

DOI:10.1038/tp.2011.26

Bipolar disorder (BD) is a severe mental disorder characterized by recurrent episodes of mania and depression. Serotonin transporter (HTT) is a target of antidepressants and is one of the strongest candidate molecules of mood disorder, however, genetic study showed equivocal results. Here, we performed promoter-wide DNA methylation analysis of lymphoblastoid cell lines (LCLs) derived from two pairs of monozygotic twins discordant for BD. To rule out the possible discordance of copy number variation (CNV) between twins, we performed CNV analysis and found the copy number profiles were nearly identical between the twin pairs except for immunoglobulin-related regions. Among the three genes we obtained as candidate regions showing distinct difference of DNA methylation between one of the two pairs, hypermethylation of SLC6A4, encoding HTT, in the bipolar twin was only confirmed by bisulfite sequencing. Then, promoter hypermethylation of SLC6A4 in LCLs of BD patients was confirmed in a case–control analysis. DNA methylation of SLC6A4 was significantly correlated with its mRNA expression level in individuals with the S/S genotype of HTTLPR, and mRNA expression level was lower in BD patients carrying the S/S genotype. Finally, DNA methylation of the same site was also higher in the postmortem brains of BD patients. This is the first study to report the role of epigenetic modification of SLC6A4 in BD using an unbiased approach, which provides an insight for its pathophysiology.

Gene expression analysis in lymphoblastoid cells as a potential biomarker of bipolar disorder

Co-reporter:Tadafumi Kato, Akiko Hayashi-Takagi, Tomoko Toyota, Takeo Yoshikawa and Kazuya Iwamoto

Journal of Human Genetics 2011 56(11) pp:779-783

Publication Date(Web):August 25, 2011

DOI:10.1038/jhg.2011.101

Although there is an urgent need for biological diagnosis of bipolar disorder (BD), there have been no established biomarkers. Gene expression analysis in lymphoblastoid cells (LCLs) would be a promising candidate for biomarkers. In this study, 17 candidate genes were measured in the LCLs of patients with BD. Using the data of the first set of samples (13 patients with bipolar I disorder and 21 controls), three genes, ANK3, RASGRP1 and POLG1, were selected by the logistic regression analysis with a stepwise method. Using the discriminant function generated by this analysis, the first sample was discriminated with the sensitivity of 76% and specificity of 85%. By applying the same function to the second sample set (18 patients with bipolar I and 37 controls), bipolar I disorder could be discriminated from the controls with the sensitivity of 44% and specificity of 81% (χ2=3.97, P=0.046). This study was the first to suggest a possible role of gene expression analysis of ANK3, RASGRP1 and POLG1 in the LCLs as potential biomarkers of BD.

Association of ANK3 with bipolar disorder confirmed in East Asia

Co-reporter:Atsushi Takata;Se Hyun Kim;Norio Ozaki;Nakao Iwata;Hiroshi Kunugi;Toshiya Inada;Hiroshi Ujike;Kazuhiko Nakamura;Norio Mori;Yong Min Ahn;Eun-Jeong Joo;Joo Yun Song;Shigenobu Kanba;Takeo Yoshikawa;Yong Sik Kim

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2011 Volume 156( Issue 3) pp:312-315

Publication Date(Web):

DOI:10.1002/ajmg.b.31164

Abstract

Results of genome-wide association studies (GWASs) for bipolar disorder (BD) have indicated ANK3 as one of the most promising candidates for a susceptibility gene. In this study, we performed genetic association analysis of two single-nucleotide polymorphisms (SNPs) in ANK3 (rs1938526 and rs10994336), whose genome-wide significant associations were reported in a previous meta-analysis of GWASs, using genotyping data of Korean and Japanese case–control samples and a part of data from a GWAS in Han-Chinese from Taiwan. The total number of participants was 2,212 cases (352 from Korea, 860 from Japan, and 1,000 from Taiwan) and 2,244 controls (349 from Korea, 895 from Japan, and 1,000 from Taiwan). We could not detect any significant difference of allele frequency in individual analyses using each of the three populations. However, when we combined the three data sets and performed a meta-analysis, rs1938526 showed nominally significant association (P = 0.048, odds ratio = 1.09). The over-represented allele in BD was same as that reported in Caucasian GWASs. On the other hand, any significant association was not detected in rs10994336. This discrepancy between two SNPs may be explained by the different degree of linkage disequilibrium between Asian and Caucasian. These findings further supported the association between ANK3 and BD, and also suggested the genomic region around rs1938526 as a common risk locus across ethnicities. © 2011 Wiley-Liss, Inc.

Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia

Co-reporter:Atsushi Takata;Maiko Kato;Masayuki Nakamura;Takeo Yoshikawa

Genome Biology 2011 Volume 12( Issue 9) pp:

Publication Date(Web):2011 September

DOI:10.1186/gb-2011-12-9-r92

Whole-exome sequencing using next-generation technologies has been previously demonstrated to be able to detect rare disease-causing variants. Progressive external ophthalmoplegia (PEO) is an inherited mitochondrial disease that follows either autosomal dominant or recessive forms of inheritance (adPEO or arPEO). AdPEO is a genetically heterogeneous disease and several genes, including POLG1 and C10orf2/Twinkle, have been identified as responsible genes. On the other hand, POLG1 was the only established gene causing arPEO with mitochondrial DNA deletions. We previously reported a case of PEO with unidentified genetic etiology. The patient was born of a first-cousin marriage. Therefore, the recessive form of inheritance was suspected.To identify the disease-causing variant in this patient, we subjected the patient's DNA to whole-exome sequencing and narrowed down the candidate variants using public data and runs of homozygosity analysis. A total of 35 novel, putatively functional variants were detected in the homozygous segments. When we sorted these variants by the conservation score, a novel missense variant in RRM2B, whose heterozygous rare variant had been known to cause adPEO, was ranked at the top. The list of novel, putatively functional variants did not contain any other variant in genes encoding mitochondrial proteins registered in MitoCarta.Exome sequencing efficiently and effectively identified a novel, homozygous missense variant in RRM2B, which was strongly suggested to be causative for arPEO. The findings in this study indicate arPEO to be a genetically heterogeneous disorder, as is the case for adPEO.

Effect of mood stabilizers on gene expression in lymphoblastoid cells

Co-reporter:Hiroko Sugawara;Kazuya Iwamoto;Miki Bundo

Journal of Neural Transmission 2010 Volume 117( Issue 2) pp:155-164

Publication Date(Web):2010 February

DOI:10.1007/s00702-009-0340-8

Lithium and valproate are widely used as effective mood stabilizers for the treatment of bipolar disorder. To elucidate the common molecular effect of these drugs on non-neuronal cells, we studied the gene expression changes induced by these drugs. Lymphoblastoid cell cultures derived from lymphocytes harvested from three healthy subjects were incubated in medium containing therapeutic concentrations of lithium (0.75 mM) or valproate (100 μg ml−1) for 7 days. Gene expression profiling was performed using an Affymetrix HGU95Av2 array containing approximately 12,000 probe sets. We identified 44 and 416 genes that were regulated by lithium and valproate, respectively. Most of the genes were not commonly affected by the two drugs. Among the 18 genes commonly altered by both drugs, vascular endothelial growth factor A (VEGFA), which is one of the VEGF gene isoforms, showed the largest downregulation. Our findings indicate that these two structurally dissimilar mood stabilizers, lithium, and valproate, alter VEGFA expression. VEGFA might be a useful biomarker of their effects on peripheral tissue.

Genetic variation of melatonin productivity in laboratory mice under domestication

Co-reporter:Takaoki Kasahara;Kuniya Abe;Kazuyuki Mekada;Atsushi Yoshiki;

Proceedings of the National Academy of Sciences 2010 107(14) pp:6412-6417

Publication Date(Web):March 22, 2010

DOI:10.1073/pnas.0914399107

Melatonin is a pineal hormone produced at night; however, many strains of laboratory mice are deficient in melatonin. Strangely enough, the gene encoding HIOMT enzyme (also known as ASMT) that catalyzes the last step of melatonin synthesis is still unidentified in the house mouse (Mus musculus) despite the completion of the genome sequence. Here we report the identification of the mouse Hiomt gene, which was mapped to the pseudoautosomal region (PAR) of sex chromosomes. The gene was highly polymorphic, and nonsynonymous SNPs were found in melatonin-deficient strains. In C57BL/6 strain, there are two mutations, both of which markedly reduce protein expression. Mutability of the Hiomt likely due to a high recombination rate in the PAR could be the genomic basis for the high prevalence of melatonin deficiency. To understand the physiologic basis, we examined a wild-derived strain, MSM/Ms, which produced melatonin more under a short-day condition than a long-day condition, accompanied by increased Hiomt expression. We generated F2 intercrosses between MSM/Ms and C57BL/6 strains and N2 backcrosses to investigate the role of melatonin productivity on the physiology of mice. Although there was no apparent effect of melatonin productivity on the circadian behaviors, testis development was significantly promoted in melatonin-deficient mice. Exogenous melatonin also had the antigonadal action in mice of a melatonin-deficient strain. These findings suggest a favorable impact of melatonin deficiency due to Hiomt mutations on domestic mice in breeding colonies.

Mitochondrial DNA haplogroup analysis in patients with bipolar disorder

Co-reporter:An-a Kazuno;Kae Munakata;Kanako Mori;Shinichiro Nanko;Hiroshi Kunugi;Kazuhiko Nakamura;Norio Mori;Kazuo Yamada;Takeo Yoshikawa;Nobumasa Kato

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2009 Volume 150B( Issue 2) pp:243-247

Publication Date(Web):

DOI:10.1002/ajmg.b.30804

Abstract

Several lines of evidence support mitochondrial dysfunction in bipolar disorder. Elevated calcium level in platelets is reported in this disease. To verify mitochondrial DNA (mtDNA) haplogroups characteristic to bipolar disorder, we sequenced mtDNA of seven regions and performed haplogroup analysis in 195 patients with bipolar disorder and 255 controls. They belonged to 16 major mtDNA haplogroups, A, B4, B5, C, D4, D5, F, G, M7, M8, M9, M10-12, N9a, N9b, Y, and Z. The logistic regression analysis revealed that the haplogroup N9a was over-represented in bipolar disorder. We also performed a case–control study for two functional mtDNA polymorphisms, mtDNA5460G > A and 12358A > G, that altered intracellular calcium dynamics. While the mtDNA5460G > A polymorphism was not associated with bipolar disorder, the mtDNA12358A > G polymorphism was associated with bipolar disorder in 199 patients with bipolar disorder and 260 controls. However, this association was not replicated in an independent sample set. Possible significances of these findings are discussed. © 2008 Wiley-Liss, Inc.

Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins

Co-reporter:G Kuratomi, K Iwamoto, M Bundo, I Kusumi, N Kato, N Iwata, N Ozaki and T Kato

Molecular Psychiatry 2008 13(4) pp:429-441

Publication Date(Web):May 1, 2007

DOI:10.1038/sj.mp.4002001

To search DNA methylation difference between monozygotic twins discordant for bipolar disorder, we applied a comprehensive genome scan method, methylation-sensitive representational difference analysis (MS-RDA) to lymphoblastoid cells derived from the twins. MS-RDA isolated 10 DNA fragments derived from 5′ region of known genes/ESTs. Among these 10 regions, four regions showed DNA methylation differences between bipolar twin and control co-twin confirmed by bisulfite sequencing. We performed a case–control study of DNA methylation status of these four regions by pyrosequencing. Two regions, upstream regions of spermine synthase (SMS) and peptidylprolyl isomerase E-like (PPIEL) (CN265253), showed aberrant DNA methylation status in bipolar disorder. SMS, a gene on X chromosome, showed significantly higher DNA methylation level in female patients with bipolar disorder compared with control females. However, there was no difference of mRNA expression. In PPIEL, DNA methylation level was significantly lower in patients with bipolar II disorder than in controls. The expression level of PPIEL was significantly higher in bipolar II disorder than in controls. We found strong inverse correlation between gene expression and DNA methylation levels of PPIEL. These results suggest that altered DNA methylation statuses of PPIEL might have some significance in pathophysiology of bipolar disorder.

Up-regulation of ADM and SEPX1 in the lymphoblastoid cells of patients in monozygotic twins discordant for schizophrenia

Co-reporter:Chihiro Kakiuchi;Mizuho Ishiwata;Shinichiro Nanko;Norio Ozaki;Nakao Iwata;Tadashi Umekage;Mamoru Tochigi;Kazuhisa Kohda;Tsukasa Sasaki;Akira Imamura;Yuji Okazaki

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2008 Volume 147B( Issue 5) pp:557-564

Publication Date(Web):

DOI:10.1002/ajmg.b.30643

Abstract

The contribution of genetic factors to schizophrenia is well established and recent studies have indicated several strong candidate genes. However, the pathophysiology of schizophrenia has not been totally elucidated yet. To date, studies of monozygotic twins discordant for schizophrenia have provided insight into the pathophysiology of this illness; this type of study can exclude inter-individual variability and confounding factors such as effects of drugs. In this study we used DNA microarray analysis to examine the mRNA expression patterns in the lymphoblastoid (LB) cells derived from two pairs of monozygotic twins discordant for schizophrenia. From five independent replicates for each pair of twins, we selected five genes, which included adrenomedullin (ADM) and selenoprotein X1 (SEPX1), as significantly changed in both twins with schizophrenia. Interestingly, ADM was previously reported to be up-regulated in both the LB cells and plasma of schizophrenic patients, and SEPX1 was included in the list of genes up-regulated in the peripheral blood cells of schizophrenia patients by microarray analysis. Then, we performed a genetic association study of schizophrenia in the Japanese population and examined the copy number variations, but observed no association. These findings suggest the possible role of ADM and SEPX1 as biomarkers of schizophrenia. The results also support the usefulness of gene expression analysis in LB cells of monozygotic twins discordant for an illness. © 2007 Wiley-Liss, Inc.

Epigenetics in mood disorders

Co-reporter:Patrick O. McGowan

Environmental Health and Preventive Medicine 2008 Volume 13( Issue 1) pp:16-24

Publication Date(Web):2008 January

DOI:10.1007/s12199-007-0002-0

Depression develops as an interaction between stress and an individual’s vulnerability to stress. The effect of early life stress and a gene–environment interaction may play a role in the development of stress vulnerability as a risk factor for depression. The epigenetic regulation of the promoter of the glucocorticoid receptor gene has been suggested as a molecular basis of such stress vulnerability. It has also been suggested that antidepressive treatment, such as antidepressant medication and electroconvulsive therapy, may be mediated by histone modification on the promoter of the brain-derived neurotrophic factor gene. Clinical genetic studies in bipolar disorder suggest the role of genomic imprinting, although no direct molecular evidence of this has been reported. The role of DNA methylation in mood regulation is indicated by the antimanic effect of valproate, a histone deacetylase inhibitor, and the antidepressive effect of S-adenosyl methionine, a methyl donor in DNA methylation. Studies of postmortem brains of patients have implicated altered DNA meA methylation of the promoter region of membrane-bound catechol-O-methyltransferase in bipolar disorder. An altered DNA methylation status of PPIEL (peptidylprolyl isomerase E-like) was found in a pair of monozygotic twins discordant for bipolar disorder. Hypomethylation of PPIEL was also found in patients with bipolar II disorder in a case control analysis. These fragmentary findings suggest the possible role of epigenetics in mood disorders. Further studies of epigenetics in mood disorders are warranted.

Association analysis of HSP90B1 with bipolar disorder

Co-reporter:Chihiro Kakiuchi;Mizuho Ishiwata;Shinichiro Nanko

Journal of Human Genetics 2007 Volume 52( Issue 10) pp:794-803

Publication Date(Web):2007 October

DOI:10.1007/s10038-007-0188-4

Pathophysiological role of endoplasmic reticulum (ER) stress response signaling has been suggested for bipolar disorder. The goal of this study was to test the genetic association between bipolar disorder and an ER chaperone gene, HSP90B1 (GRP94/gp96), which is located on a candidate locus, 12q23.3. We tested the genetic association between bipolar disorder and HSP90B1 by case-control studies in two independent Japanese sample sets and by a transmission disequilibrium test (TDT) in NIMH Genetics initiative bipolar trio samples (NIMH trios). We also performed gene expression analysis of HSP90B1 in lymphoblastoid cells. Among the 11 SNPs tested, rs17034977 showed significant association in both Japanese sample sets. The frequency of the SNP was lower in NIMH samples than in Japanese samples and there was no significant association in NIMH trios. Gene expression analysis of HSP90B1 in lymphoblastoid cells suggested a possible relationship between the associated SNP and mRNA levels. HSP90B1 may have a pathophysiological role in bipolar disorder in the Japanese population, though further study will be needed to understand the underlying functional mechanisms.

Mice with neuron-specific accumulation of mitochondrial DNA mutations show mood disorder-like phenotypes

Co-reporter:T Kasahara, M Kubota, T Miyauchi, Y Noda, A Mouri, T Nabeshima and T Kato

Molecular Psychiatry 2006 11(6) pp:577-593

Publication Date(Web):April 18, 2006

DOI:10.1038/sj.mp.4001824

There is no established genetic model of bipolar disorder or major depression, which hampers research of these mood disorders. Although mood disorders are multifactorial diseases, they are sometimes manifested by one of pleiotropic effects of a single major gene defect. We focused on chronic progressive external ophthalmoplegia (CPEO), patients with which sometimes have comorbid mood disorders. Chronic progressive external ophthalmoplegia is a mitochondrial disease, which is accompanied by accumulation of mitochondrial DNA (mtDNA) deletions caused by mutations in nuclear-encoded genes such as POLG (mtDNA polymerase). We generated transgenic mice, in which mutant POLG was expressed in a neuron-specific manner. The mice showed forebrain-specific defects of mtDNA and had altered monoaminergic functions in the brain. The mutant mice exhibited characteristic behavioral phenotypes, a distorted day–night rhythm and a robust periodic activity pattern associated with estrous cycle. These abnormal behaviors resembling mood disorder were worsened by tricyclic antidepressant treatment and improved by lithium, a mood stabilizer. We also observed antidepressant-induced mania-like behavior and long-lasting irregularity of activity in some mutant animals. Our data suggest that accumulation of mtDNA defects in brain caused mood disorder-like mental symptoms with similar treatment responses to bipolar disorder. These findings are compatible with mitochondrial dysfunction hypothesis of bipolar disorder.

A family-based and case-control association study of SOX10 in schizophrenia

Co-reporter:Kazuya Iwamoto;Miki Bundo;Kazuo Yamada;Hitomi Takao;Yoshimi Iwayama;Takeo Yoshikawa

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2006 Volume 141B(Issue 5) pp:

Publication Date(Web):1 JUN 2006

DOI:10.1002/ajmg.b.30304

Downregulation of oligodendrocyte-related genes in postmortem brains of patients with schizophrenia has been reported by several DNA microarray studies. We recently reported that enhanced DNA methylation of SOX10, which encodes a transcription factor responsible for terminal differentiation of oligodendrocyte, correlated with lower expression of SOX10 and other oligodendrocyte-related genes. Although we ruled out the possible role of SNPs of SOX10 in the altered expression and epigenetic status of oligodendrocyte genes by mutation screening of the SOX10 gene, it is not known whether its genetic polymorphisms contribute to susceptibility to schizophrenia. Here we performed a case-control and family-based association study of SOX10 in Japanese patients with schizophrenia using six SNPs and one microsatellite marker. None of these markers showed significant associations with schizophrenia by case-control or family-based association study. Haplotype analysis did not reveal significant associations between the two groups. We concluded that genetic variations in the SOX10 gene do not contribute to susceptibility to Japanese schizophrenia. © 2006 Wiley-Liss, Inc.

Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with schizophrenia in the Japanese population

Co-reporter:Shinsuke Washizuka;Mizue Kametani;Tsukasa Sasaki;Mamoru Tochigi;Tadashi Umekage;Kazuhisa Kohda

American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 2006 Volume 141B(Issue 3) pp:

Publication Date(Web):28 FEB 2006

DOI:10.1002/ajmg.b.30285

Schizophrenia and bipolar disorder share common genetic background. Several loci such as 18p11, 13q32, and 22q11–13 were commonly linked with these diseases. Since mitochondrial dysfunction has been suggested in both of these disorders, NDUFV2 at 18p11, encoding a subunit of the complex I, NADH ubiquinone oxidoreductase, is a candidate gene for these diseases. We previously reported that single nucleotide polymorphisms (SNPs) in the upstream region of NDUFV2 were associated with bipolar disorder in Japanese. The association of haplotype consisting of two SNPs, −3542G > A and −602G > A, with bipolar disorder was also seen both in Japanese and the National Institute of Mental Health Pedigrees trios. In this study, 2 polymorphisms, −3542G > A and −602G > A, were investigated in 229 schizophrenic patients as compared with controls. Individual genotypes were not associated with schizophrenia. However, the haplotype consisting of these two SNPs were significantly associated with schizophrenia. These results suggested that inter-individual variation of the genomic sequence of the promoter region of NDUFV2 might be a genetic risk factor common to bipolar disorder and schizophrenia. © 2006 Wiley-Liss, Inc.

Gene expression and association analyses of LIM (PDLIM5) in bipolar disorder and schizophrenia

Co-reporter:T Kato, Y Iwayama, C Kakiuchi, K Iwamoto, K Yamada, Y Minabe, K Nakamura, N Mori, K Fujii, S Nanko and T Yoshikawa

Molecular Psychiatry 2005 10(11) pp:1045-1055

Publication Date(Web):July 26, 2005

DOI:10.1038/sj.mp.4001719

We previously reported that expression level of LIM (ENH, PDLIM5) was significantly and commonly increased in the brains of patients with bipolar disorder, schizophrenia, and major depression. Expression of LIM was decreased in the lymphoblastoid cells derived from patients with bipolar disorders and schizophrenia. LIM protein reportedly plays an important role in linking protein kinase C with calcium channel. These findings suggested the role of LIM in the pathophysiology of bipolar disorder and schizophrenia. To further investigate the role of LIM in these mental disorders, we performed a replication study of gene expression analysis and performed genetic association studies. Upregulation of LIM was confirmed in the independent sample set obtained from Stanley Array Collection. No effect of sample pH or medication was observed. Genetic association study revealed the association of single nucleotide polymorphism (SNP)1 (rs10008257) with bipolar disorder. In an independent sample set, SNP2 (rs2433320) close to SNP1 was associated with bipolar disorder. In total samples, haplotype of these two SNPs was associated with bipolar disorder. No association was observed in case–control analysis and family-based association analysis in schizophrenia. These results suggest that SNPs in the upstream region of LIM may confer the genetic risk for bipolar disorder.

Molecular neurobiology of bipolar disorder: a disease of ‘mood-stabilizing neurons’?

Co-reporter:Tadafumi Kato

Trends in Neurosciences (October 2008) Volume 31(Issue 10) pp:495-503

Publication Date(Web):1 October 2008

DOI:10.1016/j.tins.2008.07.007

Although the role of a genetic factor is established in bipolar disorder, causative genes or robust genetic risk factors have not been identified. Increased incidence of subcortical hyperintensity, altered calcium levels in cells derived from patients and neuroprotective effects of mood stabilizers suggest vulnerability or impaired resilience of neurons in bipolar disorder. Mitochondrial dysfunction or impaired endoplasmic reticulum stress response is suggested to play a role in the neurons’ vulnerability. Progressive loss or dysfunction of ‘mood-stabilizing neurons’ might account for the characteristic course of the illness. The important next step in the neurobiological study of bipolar disorder is identification of the neural systems that are responsible for this disorder.

Comprehensive DNA methylation and hydroxymethylation analysis in the human brain and its implication in mental disorders

Co-reporter:Tadafumi Kato, Kazuya Iwamoto

Neuropharmacology (May 2014) Volume 80() pp:133-139

Publication Date(Web):1 May 2014

DOI:10.1016/j.neuropharm.2013.12.019

•Epigenetic DNA modifications may play a role in mental disorders.•Hydroxymethylation is rich in the brain and might have a role in mental disorders.•DNA methylation status differs among tissues, brain regions and cell types.•Disease-associated changes in DNA methylation were reported in mental disorders.•To be generalized, these findings should be replicated.Covalent modifications of nucleotides, such as methylation or hydroxymethylation of cytosine, regulate gene expression. Early environmental risk factors play a role in mental disorders in adulthood. This may be in part mediated by epigenetic DNA modifications. Methods for comprehensive analysis of DNA methylation and hydroxymethylation include DNA modification methods such as bisulfite sequencing, or collection of methylated, hydroxymethylated, or unmethylated DNA by specific binding proteins, antibodies, or restriction enzymes, followed by sequencing or microarray analysis. Results from these experiments should be interpreted with caution because each method gives different result. Cytosine hydroxymethylation has different effects on gene expression than cytosine methylation; methylation of CpG islands is associated with lower gene expression, whereas hydroxymethylation in intragenic regions is associated with higher gene expression. The role of hydroxymethylcytosine is of particular interest in mental disorders because the modification is enriched in the brain and synapse related genes, and it exhibits dynamic regulation during development. Many DNA methylation patterns are conserved across species, but there are also human specific signatures. Comprehensive analysis of DNA methylation shows characteristic changes associated with tissues, brain regions, cell types, and developmental states. Thus, differences in DNA methylation status between tissues, brain regions, cell types, and developmental stages should be considered when the role of DNA methylation in mental disorders is studied. Several disease-associated changes in methylation have been reported: hypermethylation of SOX10 in schizophrenia, hypomethylation of HCG9 (HLA complex group 9) in bipolar disorder, hypermethylation of PRIMA1, hypermethylation of SLC6A4 (serotonin transporter) in bipolar disorder, and hypomethylation of ST6GALNAC1 in bipolar disorder. These findings need to be replicated in different patient populations to be generalized. Further studies including animal experiments are necessary to understand the roles of DNA methylation in mental disorders.This article is part of the Special Issue entitled ‘Neuroepigenetic Disorders’.

Regional variation in mitochondrial DNA copy number in mouse brain

Co-reporter:Satoshi Fuke, Mie Kubota-Sakashita, Takaoki Kasahara, Yasufumi Shigeyoshi, Tadafumi Kato

Biochimica et Biophysica Acta (BBA) - Bioenergetics (March 2011) Volume 1807(Issue 3) pp:270-274

Publication Date(Web):March 2011

DOI:10.1016/j.bbabio.2010.11.016

Survey of the effect of genetic variations on gene expression in human prefrontal cortex and its application to genetics of psychiatric disorders

Co-reporter:Kazuya Iwamoto, Junko Ueda, Miki Bundo, Toshio Kojima, Tadafumi Kato

Neuroscience Research (June 2011) Volume 70(Issue 2) pp:238-242

Publication Date(Web):1 June 2011

DOI:10.1016/j.neures.2011.02.012

Identifying the genetic basis of gene expression variation in the human brain is important for understanding brain physiology and pathophysiology. We investigated the genetic basis of gene expression variation in human prefrontal cortex using single nucleotide polymorphisms (SNPs) and taking into consideration brain sample pH. From approximately 12,000 brain-expressed transcripts, we identified 187 cis-regulated transcripts. Some of the transcripts were identified as cis-regulated in the lymphoblastoid cells or lymphocytes, which suggests common cis-regulation across different tissues. Knowledge of genetic variations contributing to differences in gene expression in the brain would be particularly useful in the study of neuropsychiatric disorders in combination with a large-scale genome-wide association study. Using Wellcome Trust Case Control Consortium association study data, we identified SNPs associated with bipolar disorder and gene expression variation in the human brain. We found that SNPs in the AKAP10 and PRKCI genes are significantly associated with bipolar disorder and gene expression variation.

Role of mitochondrial DNA in calcium signaling abnormality in bipolar disorder

Co-reporter:Tadafumi Kato

Cell Calcium (July 2008) Volume 44(Issue 1) pp:92-102

Publication Date(Web):1 July 2008

DOI:10.1016/j.ceca.2007.11.005

Altered intracellular calcium levels are a consistent finding in studies of bipolar disorder, and recent studies point to the role of mitochondrial dysfunction, leading to the possibility that mitochondrial calcium dysregulation is involved in the pathophysiology of the disease. Although the mitochondrion is a key organelle for calcium accumulation, initial calcium signaling studies in bipolar disorder did not focus on the role of mitochondria. Later, neuroimaging and molecular genetic studies suggested the possibility that altered mitochondrial calcium regulation due to mitochondrial DNA (mtDNA) polymorphisms/mutations might be involved in the pathophysiology of bipolar disorder. Recent studies show that certain mtDNA polymorphisms alter mitochondrial calcium levels. Mutant mtDNA polymerase (Polg) transgenic mice carrying mtDNA mutations in forebrain cells show an increased calcium uptake rate in isolated mitochondria. This was found to be mediated by downregulation of cyclophilin D, a component of the mitochondrial permeability transition pore. In addition, agonist-stimulated calcium response is attenuated in hippocampal neurons of these transgenic mice. The finding that mtDNA polymorphisms and mutations affect mitochondrial calcium regulation supports the idea that mitochondrial calcium dysregulation may be involved in the pathophysiology of bipolar disorder. In this review, the history and recent findings of studies elucidating the role of mitochondrial calcium signaling in bipolar disorder are summarized.

Comprehensive survey of CNVs influencing gene expression in the human brain and its implications for pathophysiology

Co-reporter:Divya Mehta, Kazuya Iwamoto, Junko Ueda, Miki Bundo, ... Tadafumi Kato

Neuroscience Research (February 2014) Volume 79() pp:22-33

Publication Date(Web):1 February 2014

DOI:10.1016/j.neures.2013.10.009

•CNVs affecting gene expression (eCNVs) in human brain were comprehensively searched.•Rarer CNVs had more impact on gene expression.•Quarter of eCNVs located in chromosomal aberration regions causing mental disorders.Copy number variations (CNVs) contribute to neuropsychiatric diseases, which may be partly mediated by their effects on gene expression. However, few studies have assessed the influence of CNVs on gene expression in the brain. The objective was to perform an unbiased comprehensive survey of influence of CNVs on gene expression in human brain tissues. CNV regions (CNVRs) were identified in 72 individuals (23 schizophrenia, 23 bipolar disorder and 26 controls). Significant associations between the CNVRs and gene expression levels were observed for 583 CNVR-expression probe pairs (293 unique eCNVRs and 429 unique transcripts), after corrections for multiple testing and controlling the effect of the number of subjects with CNVRs by label swapping permutations. These CNVRs affecting gene expression (eCNVRs) were significantly enriched for rare/low frequency (p = 1.087 × 10−10) and gene-harboring CNVRs (p = 1.4 × 10−6). Transcripts overlapping CNVRs were significantly enriched for glutathione metabolism and oxidative stress only for cases but not for controls. Moreover, 72 (24.6%) of eCNVRs were located within the chromosomal aberration regions implicated in psychiatric-disorders: 16p11.2, 1q21.1, 22q11.2, 3q29, 15q11.2, 17q12 and 16p13.1. These results shed light on the mechanism of how CNVs confer a risk for psychiatric disorders.

Gene expression profiling of major depression and suicide in the prefrontal cortex of postmortem brains

Co-reporter:Mamoru Tochigi, Kazuya Iwamoto, Miki Bundo, Tsukasa Sasaki, ... Tadafumi Kato

Neuroscience Research (February 2008) Volume 60(Issue 2) pp:184-191

Publication Date(Web):1 February 2008

DOI:10.1016/j.neures.2007.10.010

Genome-wide gene expression analysis using DNA microarray has a great advantage to identify the genes or specific molecular cascades involved in mental diseases, including major depression and suicide. In the present study, we conducted DNA microarray analysis of major depression using postmortem prefrontal cortices. The gene expression patterns were compared between the controls and subjects with major depression. As a result, 99 genes were listed as the differentially expressed genes in major depression, of which several genes such as FGFR1, NCAM1, and CAMK2A were of interest. Gene ontology analysis suggested an overrepresentation of genes implicated in the downregulation or inhibition of cell proliferation. The present results may support the hypothesis that major depression is associated with impaired cellular proliferation and plasticity. Comparison between the controls and suicide victims with major depression, bipolar disorder, or schizophrenia was also conducted in the present study. Two genes, CAD and ATP1A3, were differentially expressed in the three comparisons in the same direction. Interestingly, these two genes were also included in the differentially expressed 99 genes in major depression. It may be worth investigating the genes in relation to suicide or major depression.

Neuronal cell-type specific DNA methylation patterns of the Cacna1c gene

Co-reporter:Masaki Nishioka, Takafumi Shimada, Miki Bundo, Wataru Ukai, ... Kazuya Iwamoto

International Journal of Developmental Neuroscience (April 2013) Volume 31(Issue 2) pp:89-95

Publication Date(Web):1 April 2013

DOI:10.1016/j.ijdevneu.2012.11.007

Gene expression of the alpha-1 subunit of the L-type voltage-gated calcium channel, CACNA1C, is known to be complexly regulated. Because CACNA1C is not only a crucial gene in normal brain function but also a promising candidate risk gene for psychiatric disorders such as bipolar disorder and schizophrenia, elucidating the molecular basis of transcriptional regulatory mechanism will be critically important. Here we examined DNA methylation status of CpG islands and a CpG island shore on mouse Cacna1c in neuronal and non-neuronal nuclei, which were separated with a fluorescent activated cell sorting technique. We found that neurons and non-neurons showed differential DNA methylation profile on a CpG island shore. This difference was evolutionarily conserved in human neuronal and non-neuronal nuclei in the prefrontal cortex, suggesting that DNA methylation status on the CpG island shore of Cacna1c may have an important role in transcript regulation.Highlights► Neurons had characteristic DNA methylation on the CpG island shore in mouse Cacna1c. ► Epigenetic signature in neuron was also observed in CACNA1C in human frontal cortex. ► Our results indicate the gene-regulatory role of CpG island shore in Cacna1c.

Association analysis of ATF4 and ATF5, genes for interacting-proteins of DISC1, in bipolar disorder

Co-reporter:Chihiro Kakiuchi, Mizuho Ishiwata, Shinichiro Nanko, Hiroshi Kunugi, Yoshio Minabe, Kazuhiko Nakamura, Norio Mori, Kumiko Fujii, Kazuo Yamada, Takeo Yoshikawa, Tadafumi Kato

Neuroscience Letters (7 May 2007) Volume 417(Issue 3) pp:316-321

Publication Date(Web):7 May 2007

DOI:10.1016/j.neulet.2007.02.054

Disrupted in schizophrenia 1 (DISC1) and its molecular cascade are implicated in the pathophysiology of schizophrenia and bipolar disorder. As interacting-proteins with DISC1, Nudel, ATF4, ATF5, LIS1, α-tubulin, PDE4B, eIF3, FEZ1, Kendrin, MAP1A and MIPT3 were identified. We previously showed the down-regulation of ATF5 in the lymphoblastoid cells derived from affected co-twin of monozygotic twins discordant for bipolar disorder. We also suggested the contribution of endoplasmic reticulum stress response pathway to the illness, and ATF4 is one of major components in the pathway. Truncated mutant DISC1 reportedly cannot interact with ATF4 and ATF5. These findings suggest the role of these genes in the pathophysiology of bipolar disorder. In this study, we tested genetic association of ATF4 and ATF5 genes with bipolar disorder by a case–control study in Japanese population (438 patients and 532 controls) and transmission disequilibrium test in 237 trio samples from NIMH Genetics Initiative Pedigrees. We also performed gene expression analysis in lymphoblastoid cells. We did not find any significant association in both genetic study and expression analysis. By the exploratory haplotype analysis, nominal association of ATF4 with bipolar II patients was observed, but it was not significant after correction of multiple testing. Contribution of common variations of ATF4 and ATF5 to the pathophysiology of bipolar disorder may be minimal if any.

Increased L1 Retrotransposition in the Neuronal Genome in Schizophrenia

Co-reporter:Miki Bundo, Manabu Toyoshima, Yohei Okada, Wado Akamatsu, ... Kazuya Iwamoto

Neuron (22 January 2014) Volume 81(Issue 2) pp:306-313

Publication Date(Web):22 January 2014

DOI:10.1016/j.neuron.2013.10.053

•Increased L1 copy number in brains of patients with schizophrenia•Increased L1 content in animal models for neurodevelopmental models of schizophrenia•Increased L1 content in iPS-derived neurons of schizophrenia patients with 22q11 deletion•L1 insertions in patients were found in synapse or schizophrenia-related genesRecent studies indicate that long interspersed nuclear element-1 (L1) are mobilized in the genome of human neural progenitor cells and enhanced in Rett syndrome and ataxia telangiectasia. However, whether aberrant L1 retrotransposition occurs in mental disorders is unknown. Here, we report high L1 copy number in schizophrenia. Increased L1 was demonstrated in neurons from prefrontal cortex of patients and in induced pluripotent stem (iPS) cell-derived neurons containing 22q11 deletions. Whole-genome sequencing revealed brain-specific L1 insertion in patients localized preferentially to synapse- and schizophrenia-related genes. To study the mechanism of L1 transposition, we examined perinatal environmental risk factors for schizophrenia in animal models and observed an increased L1 copy number after immune activation by poly-I:C or epidermal growth factor. These findings suggest that hyperactive retrotransposition of L1 in neurons triggered by environmental and/or genetic risk factors may contribute to the susceptibility and pathophysiology of schizophrenia.

Animal models of bipolar disorder

Co-reporter:Tadafumi Kato, Mie Kubota, Takaoki Kasahara

Neuroscience & Biobehavioral Reviews (2007) Volume 31(Issue 6) pp:832-842

Publication Date(Web):1 January 2007

DOI:10.1016/j.neubiorev.2007.03.003

Animal models of human diseases should meet three sets of criteria: construct validity, face validity, and predictive validity. To date, several putative animal models of bipolar disorder have been reported. They are classified into various categories: pharmacological models, nutritional models, environmental models, and genetic models. None of them, however, totally fulfills the three validity criteria, and thus may not be useful for drug development. Mounting evidence suggests that mitochondrial dysfunction has a role in bipolar disorder. To test whether accumulation of mtDNA deletions in the brain can cause bipolar disorder, we generated transgenic mice with neuron-specific expression of mutant Polg (D181A). These mice showed altered diurnal activity rhythm and periodic activity change associated with the estrous cycle. These phenotypes were worsened by administration of a tricyclic antidepressant, but improved after lithium treatment. This mouse model of bipolar disorder potentially fulfills the three validity criteria, and therefore might be used for future drug development studies.

Epigenetic Regulation of Serotonin Transporter in Psychiatric Disorders

Co-reporter:Hiroko Sugawara, Miki Bundo, Jun Ishigooka, Kazuya Iwamoto, Tadafumi Kato

Journal of Genetics and Genomics (20 July 2013) Volume 40(Issue 7) pp:325-329

Publication Date(Web):20 July 2013

DOI:10.1016/j.jgg.2012.10.002

Evaluation of whole genome amplification methods using postmortem brain samples

Co-reporter:Kazuya Iwamoto, Junko Ueda, Yoko Nakano, Miki Bundo, Wataru Ukai, Eri Hashimoto, Toshikazu Saito, Tadafumi Kato

Journal of Neuroscience Methods (15 September 2007) Volume 165(Issue 1) pp:104-110

Publication Date(Web):15 September 2007

DOI:10.1016/j.jneumeth.2007.05.029

The importance of examining genomic DNA derived from human brain has been highlighted by recent findings such as the possible link between DNA methylation and behavior or mental disorders, as well as the possible genomic differences between neurons from the same individual caused by transposons and aneuploidy. Consequently, obtaining a sufficient amount of genomic DNA derived from human brain is a critical issue for further research. Whole genome amplification (WGA) methods, by which genomic DNA is typically amplified on the order of 104–106, will be a valuable tool for providing a sufficient amount of DNA for various molecular genetic studies. Here we evaluated three methods, including both PCR-based and non-PCR based WGA, as well as DNA extraction methods using frozen postmortem brain tissue. We found that WGA products from postmortem brains can be used in molecular genetic analysis, if a particular protocol for DNA extraction is used, and the most appropriate method for WGA depends on the state of the genomic DNA to be amplified.