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International team sheds new light on biology underlying schizophrenia genes, pathways identified could inform new approaches to treatment

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As part of a multinational, collaborative effort, the Psychiatric Genetics Consortium have helped identify over 100 locations in the human genome associated with the risk of developing schizophrenia in what is the largest genomic study published on any psychiatric disorder to date. The findings, which are published online in Nature, point to biological mechanisms and pathways that may underlie schizophrenia, and could lead to new approaches to treating the disorder, which has seen little innovation in drug development in more than 60 years.

In the genomics era, research has focused on the genetic underpinnings of schizophrenia because of the disorder’s high heritability. Previous studies have revealed the complexity of the disease (with evidence suggesting that it is caused by the combined effects of many genes), and roughly two dozen genomic regions have been found to be associated with the disorder. The new study confirms those earlier findings, and expands our understanding of the genetic basis of schizophrenia and its underlying biology.  

In the genome-wide association study (GWAS) published in Nature, the authors looked at over 80,000 genetic samples from schizophrenia patients and healthy volunteers and found 108 specific locations in the human genome associated with risk for schizophrenia.  Eighty-three of those loci had not previously been linked to the disorder.

The study implicates genes expressed in brain tissue, particularly those related to neuronal and synaptic function. These include genes that are active in pathways controlling synaptic plasticity – a function essential to learning and memory – and pathways governing postsynaptic activity, such as voltage-gated calcium channels, which are involved in signaling between cells in the brain.

Additionally, the researchers found a smaller number of genes associated with schizophrenia that are active in the immune system, a discovery that offers some support for a previously hypothesized link between schizophrenia and immunological processes. The study also found an association between the disorder and the region of the genome that holds DRD2 – the gene that produces the dopamine receptor targeted by all approved medications for schizophrenia – suggesting that other loci uncovered in the study may point to additional therapeutic targets.

The study is the result of several years of work by the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC, pgc.unc.edu), an international, multi-institutional collaboration founded in 2007 to conduct broad-scale analyses of genetic data for psychiatric disease. One-third of the samples used in the study were genotyped at the Broad Institute, but a total of 55 datasets from more than 40 different contributors were needed to conduct the analysis.

The article “Biological insights from 108 schizophrenia-associated genetic loci”, Schizophrenia Working Group of the Psychiatric Genomics Consortium, was published in Nature, 2014,Vol. 511, Nr. 7510, 24.07.2014, s. 421-7.

Facts about the study

  • More than 300 authors from 34 countries are behind the article in Nature.
  • The study is based on DNA from a total of approx. 150,000 persons.
  • The dopamine receptor DRD2, which is a known molecular target for treatment, is one of the new genes identified by the researchers. Several of the other 83 new gene regions may contain other molecular targets for treatment.
  • The Danish researchers are members of the international research consortium "Schizophrenia Working Group of the Psychiatric Genomics Consortium".
  • iPSYCH researchers from Aarhus University and Mental Health Centre Sct. Hans and Bispebjerg have been participating in this collaboration as well as Statens Serum Institut (SSI).
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