TY - JOUR

T1 - Analyzing the Role of MicroRNAs in Schizophrenia in the Context of Common Genetic Risk Variants

AU - Hauberg, Mads Engel

AU - Roussos, Panos

AU - Grove, Jakob

AU - Børglum, Anders Dupont

AU - Mattheisen, Manuel

AU - Knight, Jo

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

PY - 2016/4

Y1 - 2016/4

N2 - IMPORTANCE: The recent implication of 108 genomic loci in schizophrenia marked a great advancement in our understanding of the disease. Against the background of its polygenic nature there is a necessity to identify how schizophrenia risk genes interplay. As regulators of gene expression, microRNAs (miRNAs) have repeatedly been implicated in schizophrenia etiology. It is therefore of interest to establish their role in the regulation of schizophrenia risk genes in disease-relevant biological processes.OBJECTIVE: To examine the role of miRNAs in schizophrenia in the context of disease-associated genetic variation.DESIGN, SETTING, AND PARTICIPANTS: The basis of this study was summary statistics from the largest schizophrenia genome-wide association study meta-analysis to date (83 550 individuals in a meta-analysis of 52 genome-wide association studies) completed in 2014 along with publicly available data for predicted miRNA targets. We examined whether schizophrenia risk genes were more likely to be regulated by miRNA. Further, we used gene set analyses to identify miRNAs that are regulators of schizophrenia risk genes.MAIN OUTCOMES AND MEASURES: Results from association tests for miRNA targetomes and related analyses.RESULTS: In line with previous studies, we found that similar to other complex traits, schizophrenia risk genes were more likely to be regulated by miRNAs (P < 2 × 10-16). Further, the gene set analyses revealed several miRNAs regulating schizophrenia risk genes, with the strongest enrichment for targets of miR-9-5p (P = .0056 for enrichment among the top 1% most-associated single-nucleotide polymorphisms, corrected for multiple testing). It is further of note that MIR9-2 is located in a genomic region showing strong evidence for association with schizophrenia (P = 7.1 × 10-8). The second and third strongest gene set signals were seen for the targets of miR-485-5p and miR-137, respectively.CONCLUSIONS AND RELEVANCE: This study provides evidence for a role of miR-9-5p in the etiology of schizophrenia. Its implication is of particular interest as the functions of this neurodevelopmental miRNA tie in with established disease biology: it has a regulatory loop with the fragile X mental retardation homologue FXR1 and regulates dopamine D2 receptor density.

AB - IMPORTANCE: The recent implication of 108 genomic loci in schizophrenia marked a great advancement in our understanding of the disease. Against the background of its polygenic nature there is a necessity to identify how schizophrenia risk genes interplay. As regulators of gene expression, microRNAs (miRNAs) have repeatedly been implicated in schizophrenia etiology. It is therefore of interest to establish their role in the regulation of schizophrenia risk genes in disease-relevant biological processes.OBJECTIVE: To examine the role of miRNAs in schizophrenia in the context of disease-associated genetic variation.DESIGN, SETTING, AND PARTICIPANTS: The basis of this study was summary statistics from the largest schizophrenia genome-wide association study meta-analysis to date (83 550 individuals in a meta-analysis of 52 genome-wide association studies) completed in 2014 along with publicly available data for predicted miRNA targets. We examined whether schizophrenia risk genes were more likely to be regulated by miRNA. Further, we used gene set analyses to identify miRNAs that are regulators of schizophrenia risk genes.MAIN OUTCOMES AND MEASURES: Results from association tests for miRNA targetomes and related analyses.RESULTS: In line with previous studies, we found that similar to other complex traits, schizophrenia risk genes were more likely to be regulated by miRNAs (P < 2 × 10-16). Further, the gene set analyses revealed several miRNAs regulating schizophrenia risk genes, with the strongest enrichment for targets of miR-9-5p (P = .0056 for enrichment among the top 1% most-associated single-nucleotide polymorphisms, corrected for multiple testing). It is further of note that MIR9-2 is located in a genomic region showing strong evidence for association with schizophrenia (P = 7.1 × 10-8). The second and third strongest gene set signals were seen for the targets of miR-485-5p and miR-137, respectively.CONCLUSIONS AND RELEVANCE: This study provides evidence for a role of miR-9-5p in the etiology of schizophrenia. Its implication is of particular interest as the functions of this neurodevelopmental miRNA tie in with established disease biology: it has a regulatory loop with the fragile X mental retardation homologue FXR1 and regulates dopamine D2 receptor density.

KW - Fragile X Mental Retardation Protein

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study

KW - Humans

KW - MicroRNAs

KW - Polymorphism, Single Nucleotide

KW - RNA-Binding Proteins

KW - Risk Factors

KW - Schizophrenia

KW - Journal Article

KW - Meta-Analysis

KW - Research Support, Non-U.S. Gov't

U2 - 10.1001/jamapsychiatry.2015.3018

DO - 10.1001/jamapsychiatry.2015.3018

M3 - Journal article

C2 - 26963595

VL - 73

SP - 369

EP - 377

JO - JAMA Psychiatry

JF - JAMA Psychiatry

SN - 2168-622X

IS - 4

ER -