Landmark studies reveal the clearest genetic causes of schizophrenia so far

Hundreds of thousands of people with or without schizophrenia have had their DNA analysed in two major international studies involving Danish iPSYCH. The results shed further light on the genetic roots of schizophrenia, and a picture of the fundamental causes of the serious mental disorder is emerging.

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Anders Børglum says that "the results mark an important step forward in our understanding of the origins of schizophrenia." Photo: Lars Kruse, AU Foto

Up to 30,000 Danes suffer from schizophrenia, and around one per cent of the population will at some point in their lives develop this mental disorder. But what actually causes the disorder to occur? The largest genetic studies of schizophrenia ever conducted have helped shed new light on this question.

One of the studies is called SCHEMA. In this study, the researchers identified extremely rare protein-disrupting mutations in ten genes which increase a person's risk of developing schizophrenia significantly – with the risk being up to fifty times greater in some cases.

"Among the general population, a person has around a one per cent risk of developing schizophrenia, but if you carry one of these very rare mutations, the risk increases to five, ten, twenty, or all the way up to approximately fifty per cent," explains Anders Børglum, who is one of the driving forces behind the Danish contribution, and continues:

"Identifying these ten genes is a landmark moment in schizophrenia research, because each of them provides a solid foundation for initiating a targeted study of the specific biological processes that are disrupted."

Linked to schizophrenia

The second study analysed millions of commonly occurring DNA variations in 76,755 people with schizophrenia and 243,649 people without, and here the researchers found a much larger number of genetic links to schizophrenia than ever before, in 287 different areas in the genome, including several of the ones that the SCHEMA study pointed to.

The individual commonly occurring DNA variation in the 287 areas increases the risk of schizophrenia very little (approx. 1.05-1.10 times), but together they constitute the largest part of the genetic risk.

By utilising detailed analyses and correlation with SCHEMA and other biological data from brain studies, the researchers were able to point to 120 specific genes which probably play a role in the development of schizophrenia.

The results have been published in the scientific journal Nature.

New view of the disease

When taken together, the studies show an emerging view that schizophrenia may be the result of a breakdown in communication in the synapses, which are the neuronal junction between two nerve cells.

"Previous research has shown correlations between schizophrenia and many anonymous DNA sequences, but it has rarely been possible to link the results to specific genes. And this is what we need to do to understand the causes of this disorder and develop new treatments," says Anders Børglum.

The studies also showed that the genetic risk of schizophrenia is seen in genes that are active in brain cells – not in other tissues or other cell types – and, according to the researchers, this suggests that it is the biological role of these cells that is crucial for developing schizophrenia. In other words, it is the development and functioning of these cells that are impaired in people with schizophrenia.

The results also suggest that this disrupted neuronal function in schizophrenia is found in many areas of the brain, which may explain the different symptoms of the disorder, such as hallucinations, delusions and difficulty thinking clearly.

“Although people with schizophrenia can recover, many don’t respond well to treatments, and they experience long-term side effects and face challenges with their mental and physical health. We hope that the results can be used to improve our understanding of the disorder and to facilitate the development of ​new treatments," says Anders Børglum, who acknowledges that there is still a long way to go in the work being done to improve the treatment of people with schizophrenia.

"The results mark an important step forward in our understanding of the origins of ​schizophrenia, and they’ll make it possible for researchers to focus on specific biological processes and neural pathways in the hunt for new therapies for this serious mental disorder. The study has shown the importance and power of ​having large amounts of samples in genetic studies to gain insight into psychiatric disorders," he says.

Background for the results:

The researchers analysed DNA from more than 320,000 people with and without schizophrenia to better understand the genes and biological processes which lie behind the condition.

Partners: The Psychiatric Genomics Consortium and the SCHEMA Consortium.

Read more about iPSYCH here:

The project is financially supported by the Lundbeck Foundation.

The scientific articles can be read in Nature:


Anders Børglum
Aarhus University, Department of Biomedicine
Mobile: (+45) 6020 2720