Zeroing in on the genetics of schizophrenia

Lead by the University of Exeter Medical School, a global research team has advanced the understanding of how genetic risk factors alter gene function in schizophrenia

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In an area that is already one of the most challenging in medicine and the life sciences—neurology—schizophrenia has been one of the most difficult conditions to understand and to treat. It is known that the neuropsychiatric disorder is often inherited and its hallmarks—episodes of psychosis and altered brain function—are also well known. But while there has been research that has identified genetic variants associated with schizophrenia, there is still great uncertainty as to which genes cause the condition and how their function is regulated.
An international study led by the University of Exeter Medical School, however, may be part of turning that lack of understanding around, having made advances in understanding the ways in which genetic risk factors alter gene function in schizophrenia. The team’s work was described in a paper published recently in Genome Biology and titled “An integrated genetic-epigenetic analysis of schizophrenia: evidence for co-localization of genetic associations and differential DNA methylation.”
The study, which used blood samples from 1,714 individuals, is the largest of its kind, Exeter maintains, adding that “It has helped to clarify which specific genes are actually affected by the genetic variants associated with schizophrenia, and provides a blueprint for researchers to undertake similar analyses for other complex diseases.”
The team included collaborators from King’s College London, University College London and the University of Aberdeen, as well as colleagues in Finland, China, Germany and the Netherlands.
According to Exeter, the team focused on both the underlying genetic sequence and DNA methylation and, by profiling genetic and regulatory variation in the same samples, the group found that many of the genetic variants previously found to be associated with schizophrenia have potential effects on gene regulation.
As the researchers wrote in the paper, “A better understanding of the molecular mechanisms underlying disease phenotypes is best achieved using an integrated functional genomics strategy, although few studies have attempted to systematically integrate genetic and epigenetic epidemiological approaches.”
In its research, the team identified epigenetic changes in 26 of 105 regions of the genome previously implicated in schizophrenia—a huge step in prioritizing specific genes for additional functional studies and as potential treatment targets.
“This study highlights the power of integrating different types of genomic data to better understand how disease-associated DNA sequence variation actually influences the way in which genes function,” said Prof. Jonathan Mill of the University of Exeter Medical School, who led the research. “Although our study focused on schizophrenia, we’re now applying this approach to other types of complex disease.”
Dr. Eilis Hannon of the University of Exeter Medical School was the lead author of the study, and she added: “It is clear that genetic studies need to look beyond simply sequencing DNA, and in this study we simultaneously profiled DNA methylation. By aligning the results from these two molecular approaches, we have generated a list of genes directly affected by schizophrenia genetic risk factors.”
As the paper concluded, “This study represents the first systematic integrated analysis of genetic and epigenetic variation in schizophrenia, introducing a methodological approach that can be used to inform epigenome-wide association study analyses of other complex traits and diseases. We demonstrate the utility of using a polygenic risk score to identify molecular variation associated with etiological variation, and of using DNA methylation quantitative trait loci to refine the functional and regulatory variation associated with schizophrenia risk variants. Finally, we present strong evidence for the co-localization of genetic associations for schizophrenia and differential DNA methylation.”

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