'10 years worth of data' help researchers nail down genes linked with schizophrenia

Precise genetic clues about schizophrenia have long eluded scientists, but new research from what researchers tout as “the largest genome-wide association study” has identified genetic mutations and changes in neuron function that could be harbingers of the neurological disease.

The massive study—which is really two complementary studies, both published Thursday in Nature—was a multi-faceted collaboration between the Psychiatric Genomics Consortium (PGC), the Broad Institute of Harvard and MIT and Cardiff University in the U.K. The first and larger arm, led primarily by the consortium and Cardiff University, united hundreds of researchers across 45 countries to analyze DNA of more than 320,000 people, nearly a quarter of which had schizophrenia. A subset of that total was further assessed by the Broad Institute and an additional, separate international consortium, SCHEMA. 

"There's 10 years' worth of data represented in these studies," said Sinéad Chapman, director of global genetics project management at the Stanley Center within the Broad Institute. 

The findings of the Cardiff-led paper found genetic links to schizophrenia in more than 280 different regions in the genome. Additionally, genetic risk was most concentrated in the neurons, brain cells that are responsible for receiving sensory information, communicating motor function and transmitting electrical signals. The team led by the Broad Institute added to these findings, identifying 10 rare mutations that disrupt proteins and can increase a person’s risk of schizophrenia. One of these mutations, scientists noted, increased the risk 20-fold. 

"Identifying these 10 genes is a watershed moment in schizophrenia research because each one of them provides a solid foundation for launching biological inquiry," said Benjamin Neale, a co-corresponding author on the SCHEMA study and another director of genetics in the Stanley Center, in a statement. “These discoveries are the starting point for developing new therapies that treat the root cause of this devastating condition."

In a primary assessment of the samples, more than 90% were either of European or East Asian descent. Samples of African American or Latino heritage made up roughly 8% of the total. A 2013 study found that African Americans had the highest lifetime prevalence rates of psychotic symptoms among racial groups, followed by Latinos.

In an email to Fierce Biotech, Michael O'Donovan, Ph.D., who led the study out of Cardiff, said the researchers were limited by what data was available but he acknowledged the gap. 

“Unfortunately, as in most areas of medicine, major ancestries are virtually or entirely missing ... it is a situation in urgent need of a remedy,” he wrote. 

The PGC, funded by the National Institute of Mental Health within the National Institutes of Health, has been conducting larger genome-wide associations since 2009. The SCHEMA consortium on the other hand has only been around for five years and focuses specifically on the exome—the portion of DNA that codes for proteins. Two of the genes highlighted in the study, GRIN2A and GRIA3, help code for a receptor on the synapse that helps neurons receive chemical signals. GRIN2A also peaks during adolescence, which is when schizophrenia symptoms can begin. 

Co-author and fellow Stanley Center director Steven Hyman noted that it’s taken scientists “years and years” to arrive at the findings released Thursday. But he poured a bit of ice water on the timing of next steps, saying it would “take yet more years” for these mutations to turn into biomarkers and eventually potential therapies. 

Meanwhile, companies are getting closer to market with new therapies that have been in development for years. Karuna Therapeutics and Sunovion, which teamed up with Otsuka Pharmaceutical last year, each have treatments in the works. Karuna’s drug, KarXT, targets muscarinic acetylcholine receptors in two different parts of the brain to both act as treatment and mitigate side effects. Sunovion designed an agonist for the TAAR1 receptor, which is expressed throughout the brain and has been found in regions tied to early disease symptoms.