Two newly discovered genes have been linked to schizophrenia while a previously known gene associated with schizophrenia risk has also been linked to autism in a massive new study.
Scientists say the findings increase our understanding of brain diseases and could lead to new treatment targets.
Importantly, this is the first known investigation to look at the risk of schizophrenia in different groups of people, especially those with African ancestry. It revealed rare harmful variations in gene proteins raise the risk of schizophrenia in all ethnic groups.
As with many neurological conditions, the exact causes of schizophrenia are varied and complex, and mostly unknown, although it seems a combination of genetic, environmental, and biological changes in the brain play a part.
"The motivation for this study was to better understand how rare genetic variants influence a person's risk for developing severe mental illness, specifically the mental illness schizophrenia," says genetic psychiatrist Alexander Charney from the Icahn School of Medicine at Mount Sinai in the US.
Recent research has shown that people with schizophrenia have more rare protein-truncating variants (PTVs) among a selection of ten genes than people who don't have schizophrenia. PTVs are DNA code changes that can cause a gene to produce a protein without essential parts, disrupting its function.
However, that study – like most genetic studies – was conducted on European populations, even though schizophrenia is common worldwide.
In the latest investigation two new risk genes, SRRM2 and AKAP11, were identified through a comparison of the gene sequences of people with schizophrenia to those of healthy people from different groups, particularly those of African ancestry.
A third gene identified in the study, PCLO, has been linked to schizophrenia in the past, but now it is known that it also increases the risk of autism. This adds to what we already know about the genetic overlap between some neurological conditions.
"It's been known that there are genetic components shared among illnesses. Clinically, genes could look different in the same family. The same variant in the same family may cause autism in one family member and schizophrenia in another," Charney says.
"The idea of the same gene having different manifestations is very interesting to us, as it could be useful when it comes to treating people in the clinic."
To come to their findings, the team conducted a meta-analysis that included 35,828 cases and 107,877 controls obtained from previously published datasets.
By pooling data from multiple studies that have examined the same phenomenon, a meta-analysis can help researchers identify patterns or inconsistencies in the findings of different studies and provide a more accurate estimate of the effect size.
Sequencing the entire genome is costly, so the researchers applied targeted gene sequencing to carefully selected genes from this data – from 11,580 people with a diagnosis of schizophrenia or schizoaffective disorders, and 10,555 people with no known diagnosis of a psychiatric disorder. The people whose genes were included in the study were not closely related, and 40 percent were non-European.
"By focusing on a subset of genes, we discovered rare damaging variants that could potentially lead to new medicines for schizophrenia," says lead author, geneticist and data analyst Dongjing Liu from Icahn School of Medicine at Mount Sinai.
"Also significant: studying people of various ancestral backgrounds, we found that rare damaging variants in evolutionarily constrained genes confer a similar magnitude of schizophrenia risk among those different populations and that genetic factors previously established in predominantly white people have now been extended to non-whites for this debilitating disease."
Schizophrenia is a severe mental illness that affects thinking, feeling, and behavior. Usually starting in late adolescence or early adulthood and affecting around 7 in 1,000 people, it shortens a person's life by almost 15 years, according to statistics.
Symptoms include hearing or seeing things that aren't there, believing in things that aren't real, disorganized thinking and behavior, and a lack of motivation. The symptoms can be very upsetting for the person who has them and for those around them.
For many people, schizophrenia is well managed with treatment but the current medications don't work for everyone, symptoms and side effects vary and more research is needed.
The researchers plan to further investigate the clinical implications of these newly discovered genes on specific schizophrenia symptoms or behaviors and identify potential medications to target them.
Liu and colleagues conclude that the major contribution of this study to the field of genetics is demonstrating that genetic risk is uniform across ethnicities.
"Achieving diversity in human genetic research must be a top priority to prevent health disparities from worsening as findings from genetic research begin to be translated into clinical practice," they write.
This seems a promising step in the right direction.
The peer reviewed research has been published in the journal Nature Genetics.