Meta gene set enrichment analyses link miR-137-regulated pathways with schizophrenia risk.
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.
The Mind Research Network Albuquerque, NM, USA ; Department of Neurosciences, University of New Mexico Albuquerque, NM, USA.
Carrie
C
Wright
The Mind Research Network Albuquerque, NM, USA ; Department of Neurosciences, University of New Mexico Albuquerque, NM, USA ; Department of Electrical and Computer Engineering, University of New Mexico Albuquerque, NM, USA.
Vince D
VD
Calhoun
Translational Developmental Neuroscience Section, Department of Child and Adolescent Psychiatry, Faculty of Medicine, Technische Universität Dresden Dresden, Germany ; Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital Boston, MA, USA ; Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Massachusetts Institute of Technology/Harvard Medical School Charlestown, MA, USA.
Stefan
S
Ehrlich
Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine Chicago, IL, USA ; Department of Radiology, Northwestern University Feinberg School of Medicine Chicago, IL, USA.
Lei
L
Wang
The Mind Research Network Albuquerque, NM, USA ; Department of Psychology and Neuroscience Institute, Georgia State University Atlanta, GA, USA.
Jessica A
JA
Turner
Department of Neurosciences, University of New Mexico Albuquerque, NM, USA ; Department of Psychiatry, University of New Mexico Albuquerque, NM, USA.
Nora I Perrone-
NI
Bizzozero
PKA signaling; gene set enrichment analysis (GSEA); miR-137; microRNA; pathway analysis; schizophrenia