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

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          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.

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          Most cited references 62

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          MicroRNAs: target recognition and regulatory functions.

           David Bartel (2009)
          MicroRNAs (miRNAs) are endogenous approximately 23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.
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            Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets.

            We predict regulatory targets of vertebrate microRNAs (miRNAs) by identifying mRNAs with conserved complementarity to the seed (nucleotides 2-7) of the miRNA. An overrepresentation of conserved adenosines flanking the seed complementary sites in mRNAs indicates that primary sequence determinants can supplement base pairing to specify miRNA target recognition. In a four-genome analysis of 3' UTRs, approximately 13,000 regulatory relationships were detected above the estimate of false-positive predictions, thereby implicating as miRNA targets more than 5300 human genes, which represented 30% of our gene set. Targeting was also detected in open reading frames. In sum, well over one third of human genes appear to be conserved miRNA targets.
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              Most mammalian mRNAs are conserved targets of microRNAs.

              MicroRNAs (miRNAs) are small endogenous RNAs that pair to sites in mRNAs to direct post-transcriptional repression. Many sites that match the miRNA seed (nucleotides 2-7), particularly those in 3' untranslated regions (3'UTRs), are preferentially conserved. Here, we overhauled our tool for finding preferential conservation of sequence motifs and applied it to the analysis of human 3'UTRs, increasing by nearly threefold the detected number of preferentially conserved miRNA target sites. The new tool more efficiently incorporates new genomes and more completely controls for background conservation by accounting for mutational biases, dinucleotide conservation rates, and the conservation rates of individual UTRs. The improved background model enabled preferential conservation of a new site type, the "offset 6mer," to be detected. In total, >45,000 miRNA target sites within human 3'UTRs are conserved above background levels, and >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs. Mammalian-specific miRNAs have far fewer conserved targets than do the more broadly conserved miRNAs, even when considering only more recently emerged targets. Although pairing to the 3' end of miRNAs can compensate for seed mismatches, this class of sites constitutes less than 2% of all preferentially conserved sites detected. The new tool enables statistically powerful analysis of individual miRNA target sites, with the probability of preferentially conserved targeting (P(CT)) correlating with experimental measurements of repression. Our expanded set of target predictions (including conserved 3'-compensatory sites), are available at the TargetScan website, which displays the P(CT) for each site and each predicted target.

                Author and article information

                Front Genet
                Front Genet
                Front. Genet.
                Frontiers in Genetics
                Frontiers Media S.A.
                20 April 2015
                : 6
                1The Mind Research Network Albuquerque, NM, USA
                2Department of Neurosciences, University of New Mexico Albuquerque, NM, USA
                3Department of Electrical and Computer Engineering, University of New Mexico Albuquerque, NM, USA
                4Translational Developmental Neuroscience Section, Department of Child and Adolescent Psychiatry, Faculty of Medicine, Technische Universität Dresden Dresden, Germany
                5Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital Boston, MA, USA
                6Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Charlestown, MA, USA
                7Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine Chicago, IL, USA
                8Department of Radiology, Northwestern University Feinberg School of Medicine Chicago, IL, USA
                9Department of Psychology and Neuroscience Institute, Georgia State University Atlanta, GA, USA
                10Department of Psychiatry, University of New Mexico Albuquerque, NM, USA
                Author notes

                Edited by: Valerie Knopik, Rhode Island Hospital, USA

                Reviewed by: Judith Ann Badner, University of Chicago, USA; Nicholas Bray, King's College London, UK; Ney Alliey-Rodriguez, University of Chicago, USA

                *Correspondence: Jessica A. Turner, Department of Psychology, Georgia State University, Urban Life Building, 11th floor, 140 Decatur Street, PO Box 5010, Atlanta, GA 30302, USA jturner@

                This article was submitted to Behavioral and Psychiatric Genetics, a section of the journal Frontiers in Genetics

                Copyright © 2015 Wright, Calhoun, Ehrlich, Wang, Turner and Perrone-Bizzozero.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Figures: 2, Tables: 3, Equations: 0, References: 62, Pages: 10, Words: 7456
                Original Research


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