Researchers have identified three novel genetic associations with schizophrenia, according to a new study published this week in Nature Genetics. The researchers investigated genetic associations with the condition across a large, diverse group of individuals, eventually identifying two rare variants linked with the illness and a third that is associated with both schizophrenia and autism.
A lack of diversity
Schizophrenia is a debilitating mental disorder, with symptoms including hallucinations, paranoia and withdrawal from social settings. The condition is thought to affect up to 1% of the adult population. Extensive research into the illness has led to the identification of various risk genes. One such study, known as SCHEMA, has recently identified 10 genes implicated in schizophrenia risk. However, most previous genome-wide association studies have typically focused on white European populations, including SCHEMA. This lack of diversity means the results of these studies do not accurately reflect the global genetic risk for schizophrenia.
The researchers from the Icahn School of Medicine investigated 161 genes known to be implicated in schizophrenia in a diverse 11,000 case cohort – over 60% of the group were non-European. Further to this, they also conducted a meta-analysis of previous genetic studies. This data included over 35,000 cases and almost triple the number of controls. Moreover, the large dataset included a significant number of individuals of African descent.
The work revealed that, in these datasets, rare truncating protein variants (PTVs) were enriched in schizophrenia patients. This is a subset of variation that has not been effectively assessed in diverse populations until now. Specifically, the researchers identified PTVs in two genes – SRRM2 and AKAP11 – that have not been previously implicated in schizophrenia risk. The two genes have however been linked to Alzheimer’s disease and bipolar disorder, respectively. The risk was conserved across the cohort, providing a globally relevant genetic basis for schizophrenia for the first time.
Alongside this, the team identified a gene – PCLO – that is linked to schizophrenia in some patients, and autism in others.
By identifying risk loci that are common across populations, and understanding how they contribute to disease, there is potential to identify or develop drugs that can effectively treat the condition regardless of one’s ancestry. Author Alexander Charney stated: “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.”
The link between the PCLO gene and both schizophrenia and autism also poses intriguing questions, namely in how the same mutation can manifest in distinct ways in different individuals. Speaking of the implications of this finding, Charney noted: “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. 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.” The next steps are to elucidate the clinical significance of the findings and discover if the mutations are linked to a particular symptom or characteristic of either condition.