Genetic variants linked with schizophrenia have impact in healthy carriers

Genetic variants associated with schizophrenia and autism still have an impact on cognitive skills and brain structure in people who carry the genes but do not suffer from these conditions. This is one of the main findings from research published Nature by scientists from the NEWMEDS project, which is supported by the Innovative Medicines Initiative (IMI).

The findings add to our understanding of the risk factors that contribute to these conditions and could make it easier to study the neural and biochemical foundations of cognitive abilities.

It is now well known that people’s genes can influence their risk of developing neuropsychiatric disorders like autism and schizophrenia. However, the picture is far from simple – most cases of these conditions are the result of complex interactions between a number of genes and the environment. This means that there are many people in the population who carry ‘risk’ genes but remain disease free.

In this study, researchers focused on 27 genetic variants known to be associated with an increased risk of schizophrenia and/or autism. Their goal was to determine whether healthy carriers of these variants displayed any of the cognitive difficulties or brain abnormalities found in people with schizophrenia, and then use this information to find out precisely which cognitive abnormalities put carriers at risk of developing schizophrenia.

The researchers compared people with a schizophrenia diagnosis with healthy carriers of the risk variants, healthy carriers of other risk variants, as well as people who are free of the risk-associated variants. Healthy participants underwent brain scans as well as tests of cognitive skills that are known to be problematic in schizophrenia, such as attention, spatial working memory, logical memory, cognitive flexibility (the ability to think about multiple concepts or switch rapidly between different concepts), and language.

The results revealed that the cognitive abilities of healthy carriers of risk-associated genetic variants lie between those of schizophrenia patients and people without the risk variants. In addition, the brain scans showed that healthy carriers of the risk variants had brain abnormalities linked to schizophrenia and cognitive processes.

The findings suggest that the cognitive abnormalities seen in people with schizophrenia are not necessarily a consequence of the disease; rather, having these cognitive problems may be a risk factor for the disease.

"We suggest that the work presented here lends support to the idea that cognitive abnormalities are fundamental defects in schizophrenia as they are manifest in carriers of variants conferring risk of the disease who do not suffer from the disease," said lead author of the study, Kari Stefansson MD, Dr Med. and CEO of deCODE Genetics. "Furthermore, in addition to the information they may provide on disease, these sequence variants provide us with an opportunity to search systematically for the biochemical foundation of cognitive function."

The study also points to a new way of studying the biological causes of schizophrenia. Studies on schizophrenia patients are challenging because the results can be affected by the patients’ medication and their psychosis. According to the researchers, it may be easier to study the cognitive symptoms of schizophrenia and the brain structures associated with genetic risk in people who carry the genetic variants associated with the disease but do not suffer from the condition and are not on anti-psychotic medication.

"For the first time, this study offers a glimpse of how the brain effects of these genetic variants affect cognition and increase schizophrenia and autism risk," explained co-lead author of the study, Andreas Meyer-Lindenberg MD of the Central Institute of Mental Health , University of Heidelberg in Germany.

The work was carried out by the NEWMEDS ("Novel methods leading to new medications in depression and schizophrenia") project, which is supported by the Innovative Medicines Initiative, a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations (EFPIA).

IMI Executive Director Michel Goldman commented: "This new paper by IMI's NEWMEDS project demonstrates how public-private partnerships can generate findings that are not only scientifically excellent, but of relevance for the development of new drugs that are urgently needed by schizophrenia patients worldwide."