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microRNA as regulators of schizophrenia risk genes

Transcription factors and miRNAs regulate gene expression on pre- and post-transcriptional levels, respectively. They are known to have large interaction networks and play important roles in e.g. cell differentiation and tissue development. This study explores how several miRNAs and their abilities for regulating the expression of schizophrenia risk genes.

Mads Engel Hauberg, MD, PhD student, Department of Biomedicine, Aarhus University

About the study

Genome wide association studies (GWASs) have provided substantial progress in our understanding of the genetic architecture of schizophrenia and novel insights into the underlying biology. In the most recent mega-GWAS conducted by the Psychiatric Genomics Consortium 108 loci were identified, moving schizophrenia to the front of the field of complex disorder genetics. However, current evidence suggests that thousands of common risk variants are involved in the susceptibility and the 108 loci explain only a small part (less than 5%) of the overall heritability. Thus, much more of the genetic architecture remains to be revealed.

In our study we tried to reveal more of the genetics of schizophrenia by examining the role of microRNA. microRNAs are small molecules that regulate the activity of genes, which in term determines how much of the encoded proteins is made. Different microRNAs regulate different genes and therefore have a multitude of different functions. Our focus was to identify which microRNAs regulate schizophrenia risk genes. We accomplished this using a statistical method that combined knowledge about schizophrenia associated genetic variants with knowledge about which genes each microRNA regulates.

As a result we found several microRNAs that are regulators of genes enriched for schizophrenia risk. The strongest signal was seen from a microRNA called miR-9-5p. This microRNA is known to play a pivotal role in the early development of the human brain, but also play a role in the adult brain. It is known to regulate the dopamine D2 receptor, which is the main drug target of antipsychotics used for treatment of schizophrenia. Interestingly, miR-9-5p itself turned out to also to be a potential schizophrenia risk gene. That is, miR-9-5p regulates gene sets enriched for schizophrenia risk and is itself located in a recently identified risk locus. Furthermore, another research group has published a paper shortly after ours reporting that this microRNA shows a lower expression in neuronal stem cells derived from patients with schizophrenia compared to controls. Another finding worthy of mentioning is that the top microRNAs identified in our study also include miR-137. Like miR-9-5p, it is both a regulator of schizophrenia risk genes and is also itself a likely risk gene. This microRNA has been shown to be important for maintaining the plasticity in the brain and thus for learning and memory.

The article “Analyzing the Role of MicroRNAs in Schizophrenia in the Context of Common Genetic Risk Variants" was published in JAMA Psychiatry. 2016 Apr 1;73(4):369-77.

Facts about the study

  • microRNA are small RNA-molecules that down regulate gene expression by binding to messenger RNA.
  • Using data from a large-scale study of common genetics variants in schizophrenia we looked for microRNA that regulate schizophrenia risk genes.
  • We found several such microRNA with the strongest signal for miR-9-5p, miR-485-5p, and miR-137.
  • miR-9-5p, our top finding, plays a pivotal role in brain development and is itself a schizophrenia risk gene.
  • Stem cells derived from patients suffering from schizophrenia have since been shown to have a lower expression of miR-9-5p.

Further information

Mads Engel Hauberg, MD, PhD student, Department of Biomedicine, Aarhus University

E-mail: hauberg@biomed.au.dk