Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation

Nakatani, Noriaki; Hattori, Eiji; Ohnishi, Tetsuo; Dean, Brian; Iwayama, Yoshimi; Matsumoto, Izuru; Kato, Takeshi; Osumi, Noriko; Higuchi, Tetsuya; Niwa, Shin‐Ichi; Yoshikawa, Takeo

doi:10.1093/hmg/ddl118

Cited by 134 publications

(81 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…25,31,32 Together with SLC25A12 upregulation in autism, these findings suggested that SLC25A12 might be deregulated in BP and SZ. We used previously studied samples [23][24][25] to investigate SLC25A12 expression in three neocortical regions: orbitofrontal and mid-frontal gyri (BA11), mid-and inferior-frontal gyri (BA46) and the Wernicke's area of the temporal lobe (BA22). No statistically significant differences were detected by quantitative real time RT-PCR between the BP and SZ samples and controls (Supplementary Tables 4 and 5).…”

Section: Resultsmentioning

confidence: 79%

“…We studied AK2, CASQ1 and NDUFV2, which encode mitochondrial proteins; NDUFV2 has been shown to be deregulated in BP and SZ. 25,32 No significant differences in transcript levels for these three genes in BA46 and cerebellum were found between autistic and control samples (Supplementary Tables 2 and 3). SLC25A12 expression in the human embryonic telencephalon Quantitative in situ hybridization was used to investigate the pattern of SLC25A12 expression during human prenatal development. This approach can be used to detect differences in expression between regions, and gradients of expression in a given structure.…”

Section: Resultsmentioning

confidence: 97%

“…23,24 Additional samples from bipolar (n = 7), SZ (n = 7) and controls (n = 7) were obtained for BA11, BA22 and BA46, and have been described elsewhere. 25 …”

Section: Human Brain Post-mortem Samplesmentioning

confidence: 99%

See 2 more Smart Citations

SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects

Lepagnol-Bestel

Maussion

Boda³

et al. 2008

Mol Psychiatry

View full text Add to dashboard Cite

Autism is a neurodevelopmental disorder with a strong genetic component, probably involving several genes. Genome screens have provided evidence of linkage to chromosome 2q31-q33, which includes the SLC25A12 gene. Association between autism and single-nucleotide polymorphisms in SLC25A12 has been reported in various studies. SLC25A12 encodes the mitochondrial aspartate/glutamate carrier functionally important in neurons with highmetabolic activity. Neuropathological findings and functional abnormalities in autism have been reported for Brodmann's area (BA) 46 and the cerebellum. We found that SLC25A12 was expressed more strongly in the post-mortem brain tissues of autistic subjects than in those of controls, in the BA46 prefrontal cortex but not in cerebellar granule cells. SLC25A12 expression was not modified in brain subregions of bipolar and schizophrenic patients. SLC25A12 was expressed in developing human neuronal tissues, including neocortical regions containing excitatory neurons and neocortical progenitors and the ganglionic eminences that generate neocortical inhibitory interneurons. At mid-gestation, when gyri and sulci start to develop, SLC25A12 molecular gradients were identified in the lateral prefrontal and ventral temporal cortex. These fetal structures generate regions with abnormal activity in autism, including the dorsolateral prefrontal cortex (BA46), the pars opercularis of the inferior frontal cortex and the fusiform gyrus. SLC25A12 overexpression or silencing in mouse embryonic cortical neurons also modified dendrite length and the mobility of dendritic mitochondria. Our findings suggest that SLC25A12 overexpression may be involved in the pathophysiology of autism, modifying neuronal networks in specific subregions, such as the dorsolateral prefrontal cortex and fusiform gyrus, at both pre-and postnatal stages.

show abstract

Section: Resultsmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 97%

See 1 more Smart Citation

SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects

Lepagnol-Bestel

Maussion

Boda³

et al. 2008

Mol Psychiatry

View full text Add to dashboard Cite

show abstract

“…ARNTL is upstream of DBP in the circadian clock intracellular molecular machinery, driving the transcription of DBP [Ripperger and Schibler, 2006;van der Veen et al, 2006]. An increase in ARNTL gene expression was reported in postmortem brains from bipolar subjects [Nakatani et al, 2006]. Seasonal affective disorder (SAD), a variant of bipolar disorder [Magnusson and Partonen, 2005], is tied to the amount of daylight, which is a primary regulator of circadian rhythms and clock gene expression; associations between polymorphisms in the clock genes ARNTL, PER2, and NPAS2 and SAD have previously been reported [Johansson et al, 2003;Partonen et al, 2007].…”

Section: Discussionmentioning

confidence: 99%

Coming to grips with complex disorders: Genetic risk prediction in bipolar disorder using panels of genes identified through convergent functional genomics

Patel

Le-Niculescu

Koller

et al. 2010

American J of Med Genetics Pt B

View full text Add to dashboard Cite

We previously proposed and provided proof of principle for the use of a complementary approach, convergent functional genomics (CFG), combining gene expression and genetic data, from human and animal model studies, as a way of mining the existing GWAS datasets for signals that are there already, but did not reach significance using a genetics-only approach [Le-Niculescu et al., 2009b]. CFG provides a fit-to-disease prioritization of genes that leads to generalizability in independent cohorts, and counterbalances the fit-to-cohort prioritization inherent in classic genetic-only approaches, which have been plagued by poor reproducibility across cohorts. We have now extended our previous work to include more datasets of GWAS, and more recent evidence from other lines of work. In essence our analysis is the most comprehensive integration of genetics and functional genomics to date in the field of bipolar disorder. Biological pathway analyses identified top canonical pathways, and epistatic interaction testing inside these pathways has identified genes that merit future follow-up as direct interactors (intra-pathway epistasis, INPEP). Moreover, we have put together a panel of best P-value single nucleotide polymorphisms (SNPs), based on the top candidate genes we identified. We have developed a genetic risk prediction score (GRPS) based on our panel, and demonstrate how in two independent test cohorts the GRPS differentiates between subjects with bipolar disorder and normal controls, in both European-American and African-American populations. Lastly, we describe a prototype of how such testing could be used to categorize disease risk in individuals and aid personalized medicine approaches, in psychiatry and beyond.

show abstract

“…Recently, gene expression data from post mortem brains of bipolar patients were compared with those of healthy controls in two independent studies (6,7). While post mortem approaches certainly cannot reveal cyclic changes of gene expression, these studies also failed to yield a single overlapping candidate gene for bipolar disease.…”

Section: Introductionmentioning

confidence: 99%

Episode-Specific Differential Gene Expression of Peripheral Blood Mononuclear Cells in Rapid Cycling Supports Novel Treatment Approaches

Begemann

Sargin

Rossner

et al. 2008

Mol Med

View full text Add to dashboard Cite

Molecular mechanisms underlying bipolar affective disorders are unknown. Difficulties arise from genetic and phenotypic heterogeneity of patients and the lack of animal models. Thus, we focused on only one patient (n = 1) with an extreme form of rapid cycling. Ribonucleic acid (RNA) from peripheral blood mononuclear cells (PBMC) was analyzed in a three-tiered approach under widely standardized conditions. Firstly, RNA was extracted from PBMC of eight blood samples, obtained on two consecutive days within one particular episode, including two different consecutive depressive and two different consecutive manic episodes, and submitted to (1) screening by microarray hybridizations, followed by (2) detailed bioinformatic analysis, and (3) confirmation of episode-specific regulation of genes by quantitative real-time polymerase chain reaction (qRT-PCR). Secondly, results were validated in additional blood samples obtained one to two years later. Among gene transcripts elevated in depressed episodes were prostaglandin D synthetase (PTGDS) and prostaglandin D2 11-ketoreductase (AKR1C3), both involved in hibernation. We hypothesized them to account for some of the rapid cycling symptoms. A subsequent treatment approach over 5 months applying the cyclooxygenase inhibitor celecoxib (2 × 200 mg daily) resulted in reduced severity rating of both depressed and manic episodes. This case suggests that rapid cycling is a systemic disease, resembling hibernation, with prostaglandins playing a mediator role.

show abstract

Genome-wide expression analysis detects eight genes with robust alterations specific to bipolar I disorder: relevance to neuronal network perturbation

Cited by 134 publications

References 45 publications

SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects

SLC25A12 expression is associated with neurite outgrowth and is upregulated in the prefrontal cortex of autistic subjects

Coming to grips with complex disorders: Genetic risk prediction in bipolar disorder using panels of genes identified through convergent functional genomics

Episode-Specific Differential Gene Expression of Peripheral Blood Mononuclear Cells in Rapid Cycling Supports Novel Treatment Approaches

Contact Info

Product

Resources

About