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A new mouse model for mania shares genetic correlates with human bipolar disorder.

Saul MC, Gessay GM, Gammie SC - PLoS ONE (2012)

Bottom Line: We found dysregulation of multiple transcripts whose human orthologs are associated with BPD and other psychiatric disorders including schizophrenia and ADHD, including: Epor, Smarca4, Cmklr1, Cat, Tac1, Npsr1, Fhit, and P2rx7.Using a novel genome enrichment algorithm, we found enrichment in genome regions homologous to human loci implicated in BPD in replicated linkage studies including homologs of human cytobands 1p36, 3p14, 3q29, 6p21-22, 12q24, 16q24, and 17q25.Using a functional network analysis, we found dysregulation of a gene system related to chromatin packaging, a result convergent with recent human findings on BPD.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America. csaul@wisc.edu

ABSTRACT
Bipolar disorder (BPD) is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN) that naturally displays a manic phenotype, exhibiting elevated locomotor activity, increased sexual behavior, and higher forced swimming relative to control strains. Lithium chloride and olanzapine treatments attenuate this phenotype. In this study, we replicated our locomotor activity experiment, showing that MSN mice display generationally-stable mania relative to their outbred ancestral strain, hsd:ICR (ICR). We then performed a gene expression microarray experiment to compare hippocampus of MSN and ICR mice. We found dysregulation of multiple transcripts whose human orthologs are associated with BPD and other psychiatric disorders including schizophrenia and ADHD, including: Epor, Smarca4, Cmklr1, Cat, Tac1, Npsr1, Fhit, and P2rx7. RT-qPCR confirmed dysregulation for all of seven transcripts tested. Using a novel genome enrichment algorithm, we found enrichment in genome regions homologous to human loci implicated in BPD in replicated linkage studies including homologs of human cytobands 1p36, 3p14, 3q29, 6p21-22, 12q24, 16q24, and 17q25. Using a functional network analysis, we found dysregulation of a gene system related to chromatin packaging, a result convergent with recent human findings on BPD. Our findings suggest that MSN mice represent a polygenic model for the manic pole of BPD showing much of the genetic systems complexity of the corresponding human disorder. Further, the high degree of convergence between our findings and the human literature on BPD brings up novel questions about evolution by analogy in mammalian genomes.

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Genome enrichment analysis and homology of highlighted enriched clusters to the human genome.A) Genome enrichment analysis of the MSN phenotype using a novel enrichment algorithm we created for this study (see Materials and Methods). The y-axis represents the log10 inverse of the corrected binomial probability that a cluster of dysregulated genes would occur by chance. The black horizontal lines demarcate a cluster occurring by chance with a 0.001 corrected probability, consistent with a LOD or NPL score of 3 in a linkage study. Spikes above the black lines indicate dysregulated gene clusters highly unlikely to occur by chance, indicating that the genome region is significantly enriched. Corrected probabilities less than 1×10−9 are collapsed to 1×10−9. B) Shared synteny, a similar clustering of orthologous genes, between the clusters on the murine genome highlighted in orange in Fig. 4.A and human genome regions strongly implicated in BPD (see Results for details). Blue lines represent orthologous genes and their positions in the murine (upper) and human (lower) genomes.
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pone-0038128-g004: Genome enrichment analysis and homology of highlighted enriched clusters to the human genome.A) Genome enrichment analysis of the MSN phenotype using a novel enrichment algorithm we created for this study (see Materials and Methods). The y-axis represents the log10 inverse of the corrected binomial probability that a cluster of dysregulated genes would occur by chance. The black horizontal lines demarcate a cluster occurring by chance with a 0.001 corrected probability, consistent with a LOD or NPL score of 3 in a linkage study. Spikes above the black lines indicate dysregulated gene clusters highly unlikely to occur by chance, indicating that the genome region is significantly enriched. Corrected probabilities less than 1×10−9 are collapsed to 1×10−9. B) Shared synteny, a similar clustering of orthologous genes, between the clusters on the murine genome highlighted in orange in Fig. 4.A and human genome regions strongly implicated in BPD (see Results for details). Blue lines represent orthologous genes and their positions in the murine (upper) and human (lower) genomes.

Mentions: NIAID DAVID functional annotation analysis by cytoband of all genes dysregulated at P<0.01 found a significant enrichment in murine cytoband 5qF (3.789-fold enrichment, Bonferroni-corrected P-value = 7.84×10−7) in MSN mice. We found this result intriguing, but we believed this cytoband-style enrichment analysis utilized genome regions too wide to allow the assumption of classical genetic linkage. We created a new algorithm for genome enrichment analysis with much narrower partitions of the genome queried. Our novel genome enrichment analysis yields results that look very similar to a conventional genome-wide linkage or association study, and we find it useful for generating predictions for broad chromosomal regions potentially related to a given population’s phenotype. We found significant enrichment in a total of fifteen genome regions (Fig. 4.A).


A new mouse model for mania shares genetic correlates with human bipolar disorder.

Saul MC, Gessay GM, Gammie SC - PLoS ONE (2012)

Genome enrichment analysis and homology of highlighted enriched clusters to the human genome.A) Genome enrichment analysis of the MSN phenotype using a novel enrichment algorithm we created for this study (see Materials and Methods). The y-axis represents the log10 inverse of the corrected binomial probability that a cluster of dysregulated genes would occur by chance. The black horizontal lines demarcate a cluster occurring by chance with a 0.001 corrected probability, consistent with a LOD or NPL score of 3 in a linkage study. Spikes above the black lines indicate dysregulated gene clusters highly unlikely to occur by chance, indicating that the genome region is significantly enriched. Corrected probabilities less than 1×10−9 are collapsed to 1×10−9. B) Shared synteny, a similar clustering of orthologous genes, between the clusters on the murine genome highlighted in orange in Fig. 4.A and human genome regions strongly implicated in BPD (see Results for details). Blue lines represent orthologous genes and their positions in the murine (upper) and human (lower) genomes.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3366954&req=5

pone-0038128-g004: Genome enrichment analysis and homology of highlighted enriched clusters to the human genome.A) Genome enrichment analysis of the MSN phenotype using a novel enrichment algorithm we created for this study (see Materials and Methods). The y-axis represents the log10 inverse of the corrected binomial probability that a cluster of dysregulated genes would occur by chance. The black horizontal lines demarcate a cluster occurring by chance with a 0.001 corrected probability, consistent with a LOD or NPL score of 3 in a linkage study. Spikes above the black lines indicate dysregulated gene clusters highly unlikely to occur by chance, indicating that the genome region is significantly enriched. Corrected probabilities less than 1×10−9 are collapsed to 1×10−9. B) Shared synteny, a similar clustering of orthologous genes, between the clusters on the murine genome highlighted in orange in Fig. 4.A and human genome regions strongly implicated in BPD (see Results for details). Blue lines represent orthologous genes and their positions in the murine (upper) and human (lower) genomes.
Mentions: NIAID DAVID functional annotation analysis by cytoband of all genes dysregulated at P<0.01 found a significant enrichment in murine cytoband 5qF (3.789-fold enrichment, Bonferroni-corrected P-value = 7.84×10−7) in MSN mice. We found this result intriguing, but we believed this cytoband-style enrichment analysis utilized genome regions too wide to allow the assumption of classical genetic linkage. We created a new algorithm for genome enrichment analysis with much narrower partitions of the genome queried. Our novel genome enrichment analysis yields results that look very similar to a conventional genome-wide linkage or association study, and we find it useful for generating predictions for broad chromosomal regions potentially related to a given population’s phenotype. We found significant enrichment in a total of fifteen genome regions (Fig. 4.A).

Bottom Line: We found dysregulation of multiple transcripts whose human orthologs are associated with BPD and other psychiatric disorders including schizophrenia and ADHD, including: Epor, Smarca4, Cmklr1, Cat, Tac1, Npsr1, Fhit, and P2rx7.Using a novel genome enrichment algorithm, we found enrichment in genome regions homologous to human loci implicated in BPD in replicated linkage studies including homologs of human cytobands 1p36, 3p14, 3q29, 6p21-22, 12q24, 16q24, and 17q25.Using a functional network analysis, we found dysregulation of a gene system related to chromatin packaging, a result convergent with recent human findings on BPD.

View Article: PubMed Central - PubMed

Affiliation: Department of Zoology, University of Wisconsin-Madison, Madison, Wisconsin, United States of America. csaul@wisc.edu

ABSTRACT
Bipolar disorder (BPD) is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN) that naturally displays a manic phenotype, exhibiting elevated locomotor activity, increased sexual behavior, and higher forced swimming relative to control strains. Lithium chloride and olanzapine treatments attenuate this phenotype. In this study, we replicated our locomotor activity experiment, showing that MSN mice display generationally-stable mania relative to their outbred ancestral strain, hsd:ICR (ICR). We then performed a gene expression microarray experiment to compare hippocampus of MSN and ICR mice. We found dysregulation of multiple transcripts whose human orthologs are associated with BPD and other psychiatric disorders including schizophrenia and ADHD, including: Epor, Smarca4, Cmklr1, Cat, Tac1, Npsr1, Fhit, and P2rx7. RT-qPCR confirmed dysregulation for all of seven transcripts tested. Using a novel genome enrichment algorithm, we found enrichment in genome regions homologous to human loci implicated in BPD in replicated linkage studies including homologs of human cytobands 1p36, 3p14, 3q29, 6p21-22, 12q24, 16q24, and 17q25. Using a functional network analysis, we found dysregulation of a gene system related to chromatin packaging, a result convergent with recent human findings on BPD. Our findings suggest that MSN mice represent a polygenic model for the manic pole of BPD showing much of the genetic systems complexity of the corresponding human disorder. Further, the high degree of convergence between our findings and the human literature on BPD brings up novel questions about evolution by analogy in mammalian genomes.

Show MeSH
Related in: MedlinePlus