RNA Splicing Associated With Schizophrenia Risk

RNA Splicing Associated With Schizophrenia Risk

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Highlights:
  • A research team from RIKEN Brain Science Institute have identified gene variations in the risk for schizophrenia
  • Detailed list of splicing quantitative trait loci have been developed for schizophrenia risk
  • Such genetic variation studies can be used to identify the risk for other neurological diseases too
Sections of DNA that are associated with alterations in gene expression which lead to schizophrenia have been identified in a new study published in the Journal Nature Communications. The alternate splicing mechanism is affected by the implicated loci which results in the development of schizophrenia The study promises to unearth various genes associated with the development of neurological conditions.
RNA Splicing Associated With Schizophrenia Risk

Alternative Splicing

This is a complex and prevalent mechanism which allows a single gene to be involved in the production of varied proteins. Any dysregulation of this mechanism can result in the development of many diseases. sQTLs or splicing quantitative trait loci are genetic variants which control the process of alternative splicing, though the mechanism in the brain has not been fully understood.

A research team from the RIKEN Brain Science Institute (BSI) and Yokohama City University (Japan) has put together a detailed list of sQTLs present in the brain tissue of humans and have identified that these variants were enriched among genomic regions that are associated with neurological diseases like schizophrenia.

Dr. Atsushi Takata, who is the lead author of the study, and colleagues, studied the RNA sequencing data obtained from samples of brain tissue of over 200 study participants without any known psychiatric illness. The scientists found
  • Numerous single nucleotide polymorphisms (SNPs) are common variants of genes with possible associations with the synthesis of RNA and alternative splicing. Such SNPs are termed sQTLs.
The scientists involved in the study believe that these sQTLs will aid in understanding the framework of genes in the development of psychiatric disorders.

Transcription Binding sites

The study, on further analysis of the interactions of these sQTLs with known genetic regulatory elements, aided in identifying
  • Patterns of significant depletion or enrichment of specific sites that are involved in binding histone or transcription factors.
  • Earlier genome-wide association studies that aided in identifying loci associated with schizophrenia were also found to be enriched for sQTLs; this was especially true for non-exonic sQTLs.
The findings of the study aided in proving that such neurological conditions may be caused due to changes in the splicing rather than due to alterations in the genes that affect the gene to protein expression pathway.

Earlier studies have shown that methylation QTLs (mQTL) and expression QTL (eQTL) were associated with an increase in schizophrenia risk. The current study, according to Dr. Tadafumi Kato, who is the senior author of the study, aided in determining that sQTLs were also associated with increased schizophrenia risk.

Identification of Disease Susceptibility Genes

The scientists analyzed the part of the genome that overrepresented the sQTLs and were able to locate four disease susceptibility genes which were found to be implicated in schizophrenia. The genes were
  • FXR1
  • NEK4
  • SNAP91
  • APOPT1
They were associated with the development of the nervous system, programmed cell death or apoptosis and neurotransmission. An increase in sQTLs at loci that is associated with schizophrenia is an indication that these genetic variations are linked to schizophrenia risk. However, the scientists caution that the genetic framework is extensive and the disease is very complex to be solely defined by any particular genetic polymorphism.

Schizophrenia

Schizophrenia is a psychiatric disorder.
  • It has a lifetime prevalence of 4.0 per 1,000
  • It has a morbidity risk of 7.2 per 1,000
  • It occurs during early adulthood or adolescence
  • The development of schizophrenia in the fifties is very rare
  • Prevalence is similar among males and females.
This neurological disorder is characterized by fluctuating patterns and cognitive disability. Its characteristic symptom is psychosis, along with hallucinations and delusions. The affected individual may also exhibit disorientation, emotional upheaval, speech irregularity and severe mood symptoms that range from mania to depressive episodes.

Genetics of Schizophrenia

The genetics of Schizophrenia is very complex with many genes associated with this condition. Genome wide interaction studies are necessary to identify genes as well as interactions between genes and the environment in the development of the disease.

There is a combination of rare as well as commonly found mutations that lead to the development of schizophrenia. It is important to identify these mutations as it would aid in early identification of the disease, even before the onset of symptoms. This would also aid in reducing or preventing psychotic symptoms that are often associated with schizophrenia.

References:
  1. The Role of Genetics in the Etiology of Schizophrenia - (https:www.ncbi.nlm.nih.gov/pmc/articles/PMC2826121/)


Source: Medindia

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