New Genetic Analysis Provides Clues to Schizophrenia Origins

Despite the knowledge that over 99% of human evolution occurred in Africa prior to the first migrations to Europe and Asia some 50,000 years to 100,000 years ago, few genetic studies have focused on ancestral African populations. This has created a gap in what is understood of the human genome and genetic causes of disease.

An international research team led by Jon McLellan, M.D., a professor of psychiatry at the University of Washington School of Medicine, has taken steps to address this gap as it relates to understanding schizophrenia. Earlier this year, McLellan and colleagues completed a genetic analysis of schizophrenia risk among an ancestral population in South Africa known as the Xhosa. They found that Xhosa with schizophrenia were more likely than those who did not have schizophrenia to have mutations in genes critical to synapse function. The study was published January 31 in Science.

Leveraging a long-standing partnership with the University of Cape Town in South Africa, Columbia University, and the University of Washington, McLellan and his colleagues recruited 1,826 adults who identified as Xhosa—one of the largest indigenous groups in South Africa—from health clinics across the Cape provinces in the southern part of the country to participate in the study. The participants included 909 people with schizophrenia and 917 people without the disorder. All participants had DNA samples collected and analyzed via whole-exome sequencing.

As McLellan explained, whole-exome sequencing looks for mutations in all the protein-coding parts of human genes (which represent only a tiny fraction of the whole genome). The analysis showed that Xhosa with schizophrenia were more likely to have rare and potentially damaging mutations (mutations that would significantly alter the protein structure) compared with those without schizophrenia. Many of the mutations were found in genes involved in the function of synapses—the junction between neurons that relay neurotransmitters back and forth. In particular, the mutations affected synaptic plasticity (the ability of synapses to strengthen or weaken over time is essential for the brain to learn, remember, and adapt).

McLellan noted that numerous lines of evidence have implicated synapse dysfunction as important in schizophrenia, so the identification of many synapse-related mutations in this study makes sense.

The findings also offer clues about why antipsychotics treat some but not all common schizophrenia symptoms.

“Most antipsychotics operate on the model that the individual has too much or too little neurotransmitter circulating, and the medicine corrects the imbalance,” McLellan continued. He noted that adjusting neurotransmitter levels works for some schizophrenia symptoms, such as hallucinations, but other symptoms, such as cognitive problems, might be due to faulty junctions between neurons.

Given that schizophrenia is very heterogeneous, this genetic analysis does not point to any single gene that will help guide the development of new medications, McLellan cautioned. However, as more samples are analyzed and more mutations discovered, researchers may find patterns that can point to specific biological pathways where these mutations cluster; that may provide some guidance for therapeutic strategies.

McLellan said that his consortium is preparing to submit a new grant application to conduct whole-genome studies in Xhosa to see what other genetic variants associated with schizophrenia might be present in this population.

“This wouldn’t have been possible without the help of the Xhosa community; the people were instrumental in getting this project done,” McLellan said. “Even beyond the interesting discoveries, it was a phenomenal opportunity to tour the clinics over there and work with our partners in South Africa.”

This study was supported by grants from the National Institutes of Health with additional support from the South African Medical Research Council and the Brain and Behavior Research Foundation. ■

“Genetics of Schizophrenia in the South African Xhosa” is posted here.