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Meta gene set enrichment analyses link miR-137-regulated pathways with schizophrenia risk.

Wright C, Calhoun VD, Ehrlich S, Wang L, Turner JA, Bizzozero NI - Front Genet (2015)

Bottom Line: Previous genetic pathway analyses suggest that potential targets of this microRNA (miRNA) are also highly enriched in schizophrenia-relevant biological pathways, including those involved in nervous system development and function.These results suggest that these biological pathways may be involved in the mechanisms by which this MIR137 variant enhances schizophrenia risk.Pathway-guided gene set enrichment analyses should be useful in evaluating the impact of other miRNAs and target genes in different diseases.

View Article: PubMed Central - PubMed

Affiliation: The Mind Research Network Albuquerque, NM, USA ; Department of Neurosciences, University of New Mexico Albuquerque, NM, USA.

ABSTRACT

Background: A single nucleotide polymorphism (SNP) within MIR137, the host gene for miR-137, has been identified repeatedly as a risk factor for schizophrenia. Previous genetic pathway analyses suggest that potential targets of this microRNA (miRNA) are also highly enriched in schizophrenia-relevant biological pathways, including those involved in nervous system development and function.

Methods: In this study, we evaluated the schizophrenia risk of miR-137 target genes within these pathways. Gene set enrichment analysis of pathway-specific miR-137 targets was performed using the stage 1 (21,856 subjects) schizophrenia genome wide association study data from the Psychiatric Genomics Consortium and a small independent replication cohort (244 subjects) from the Mind Clinical Imaging Consortium and Northwestern University.

Results: Gene sets of potential miR-137 targets were enriched with variants associated with schizophrenia risk, including target sets involved in axonal guidance signaling, Ephrin receptor signaling, long-term potentiation, PKA signaling, and Sertoli cell junction signaling. The schizophrenia-risk association of SNPs in PKA signaling targets was replicated in the second independent cohort.

Conclusions: These results suggest that these biological pathways may be involved in the mechanisms by which this MIR137 variant enhances schizophrenia risk. SNPs in targets and the miRNA host gene may collectively lead to dysregulation of target expression and aberrant functioning of such implicated pathways. Pathway-guided gene set enrichment analyses should be useful in evaluating the impact of other miRNAs and target genes in different diseases.

No MeSH data available.


Related in: MedlinePlus

miR-137 targets within Protein Kinase A (PKA) Signaling Pathway. This figure depicts the canonical PKA signaling pathway according to Ingenuity Pathway Analysis. Predicted miR-137 targets based on TargetScan are indicated in pink and experimentally validated regulated genes are indicated in dark blue.
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Figure 2: miR-137 targets within Protein Kinase A (PKA) Signaling Pathway. This figure depicts the canonical PKA signaling pathway according to Ingenuity Pathway Analysis. Predicted miR-137 targets based on TargetScan are indicated in pink and experimentally validated regulated genes are indicated in dark blue.

Mentions: MAGENTA analysis of a replication cohort using the MCIC (Gollub et al., 2013) and NU (Wang et al., 2013) dataset GWAS association p-values revealed one significantly enriched gene set. The PKA signaling gene set from the validated target list, including TCF4 and PTGS2, as well as MAPK1, MAPK3 (experimentally validated indirectly regulated genes), was significantly enriched with a nominal GSEA p-value of 0.003 and an FDR q-value of 0.014. Supplemental Table 6 shows the top SNPs from this analysis. As shown in Figure 2, the canonical PKA signaling pathway from IPA is enriched with predicted and validated miR-137 regulated genes, suggesting that this pathway may be involved in the mechanism of the miRNA in schizophrenia.


Meta gene set enrichment analyses link miR-137-regulated pathways with schizophrenia risk.

Wright C, Calhoun VD, Ehrlich S, Wang L, Turner JA, Bizzozero NI - Front Genet (2015)

miR-137 targets within Protein Kinase A (PKA) Signaling Pathway. This figure depicts the canonical PKA signaling pathway according to Ingenuity Pathway Analysis. Predicted miR-137 targets based on TargetScan are indicated in pink and experimentally validated regulated genes are indicated in dark blue.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4403556&req=5

Figure 2: miR-137 targets within Protein Kinase A (PKA) Signaling Pathway. This figure depicts the canonical PKA signaling pathway according to Ingenuity Pathway Analysis. Predicted miR-137 targets based on TargetScan are indicated in pink and experimentally validated regulated genes are indicated in dark blue.
Mentions: MAGENTA analysis of a replication cohort using the MCIC (Gollub et al., 2013) and NU (Wang et al., 2013) dataset GWAS association p-values revealed one significantly enriched gene set. The PKA signaling gene set from the validated target list, including TCF4 and PTGS2, as well as MAPK1, MAPK3 (experimentally validated indirectly regulated genes), was significantly enriched with a nominal GSEA p-value of 0.003 and an FDR q-value of 0.014. Supplemental Table 6 shows the top SNPs from this analysis. As shown in Figure 2, the canonical PKA signaling pathway from IPA is enriched with predicted and validated miR-137 regulated genes, suggesting that this pathway may be involved in the mechanism of the miRNA in schizophrenia.

Bottom Line: Previous genetic pathway analyses suggest that potential targets of this microRNA (miRNA) are also highly enriched in schizophrenia-relevant biological pathways, including those involved in nervous system development and function.These results suggest that these biological pathways may be involved in the mechanisms by which this MIR137 variant enhances schizophrenia risk.Pathway-guided gene set enrichment analyses should be useful in evaluating the impact of other miRNAs and target genes in different diseases.

View Article: PubMed Central - PubMed

Affiliation: The Mind Research Network Albuquerque, NM, USA ; Department of Neurosciences, University of New Mexico Albuquerque, NM, USA.

ABSTRACT

Background: A single nucleotide polymorphism (SNP) within MIR137, the host gene for miR-137, has been identified repeatedly as a risk factor for schizophrenia. Previous genetic pathway analyses suggest that potential targets of this microRNA (miRNA) are also highly enriched in schizophrenia-relevant biological pathways, including those involved in nervous system development and function.

Methods: In this study, we evaluated the schizophrenia risk of miR-137 target genes within these pathways. Gene set enrichment analysis of pathway-specific miR-137 targets was performed using the stage 1 (21,856 subjects) schizophrenia genome wide association study data from the Psychiatric Genomics Consortium and a small independent replication cohort (244 subjects) from the Mind Clinical Imaging Consortium and Northwestern University.

Results: Gene sets of potential miR-137 targets were enriched with variants associated with schizophrenia risk, including target sets involved in axonal guidance signaling, Ephrin receptor signaling, long-term potentiation, PKA signaling, and Sertoli cell junction signaling. The schizophrenia-risk association of SNPs in PKA signaling targets was replicated in the second independent cohort.

Conclusions: These results suggest that these biological pathways may be involved in the mechanisms by which this MIR137 variant enhances schizophrenia risk. SNPs in targets and the miRNA host gene may collectively lead to dysregulation of target expression and aberrant functioning of such implicated pathways. Pathway-guided gene set enrichment analyses should be useful in evaluating the impact of other miRNAs and target genes in different diseases.

No MeSH data available.


Related in: MedlinePlus