Researchers studying the biological basis of mental illness have conducted the first genomic analysis of schizophrenia in an African population, and have identified multiple rare mutations that occur more frequently in people with the condition.
The mutations are mainly in genes that are important for brain development and the brain’s synapses, tiny structures that coordinate communication between neurons. The genes match those identified in other similar studies of schizophrenia — but nearly all previous research has been conducted in European or Asian populations. The latest work was published1 in Science on 31 January.
This research is particularly important because Africa has represented a big gap in the populations that geneticists have studied, says psychiatric geneticist Andreas Meyer-Lindenberg, director of the Central Institute of Mental Health in Mannheim, Germany. He says that the work lends support to current hypotheses about the biological origins of schizophrenia, which can cause a range of symptoms including hallucinations, delusions and disordered thinking. Researchers think that each mutation might contribute a small amount to the overall risk of developing the condition, and that disruption to synapses could be crucial to the disease’s development.
Years of neglect
Over the past decade, as studies that use genome sequencing to identify the genetic basis of diseases have flourished, geneticists have come under increasing fire for failing to sample diverse populations, largely neglecting African people. Around 80% of participants in genetic studies are of European descent, and less than 3% are of African descent.
“This urgently needs more attention,” says Ambroise Wonkam, a human geneticist at the University of Cape Town, South Africa, who is also president of the African Society of Human Genetics.
This bias means that diagnostic tests and medical treatments developed on the basis of these narrow studies might not work in certain populations. For instance, a 2016 study reported2 that genetic tests which calculate a person’s risk of a deadly heart condition had often led to misdiagnosis. That was because the genes on which it was based had been identified in studies that did not include black people, who tend to have many different variants of the gene that influence risk of the disease.
Studies in diverse populations also allow researchers to build up a fuller picture of diseases. In particular, African people as a group have genomes that are much more diverse than those of other populations, and they harbour a large number of unique gene variants. This is because the vast majority of human evolution took place in Africa, where modern humans emerged. And when some people left Africa 50,000 to 100,000 years ago, only a relatively small number migrated to Europe and Asia to seed new populations. As a result, genetic diversity in these regions is lower. Research efforts — in particular the Human Heredity and Health in Africa (H3Africa) Initiative — are now trying to improve African scientists’ capacity to collect and analyse genome data from their own populations.
The latest study, conducted by researchers in South Africa and the United States, enrolled around 900 people with schizophrenia and a similar number who didn’t have the disorder, to serve as controls. All participants self-identified as Xhosa, members of a large ethnic group who live mainly in South Africa.
The researchers sequenced the portion of the participants’ genomes that encodes proteins, and searched for mutations that damage genes. Such mutations, they found, were much more prevalent in people with schizophrenia than in the control individuals, and were concentrated in genes that are highly expressed in the brain or are involved in the functioning of synapses.
The team compared its results with those obtained in a large Swedish study3 of schizophrenia that used the same methods. The studies identified similar genes, but the density of mutations in a gene were generally larger in the Xhosa participants. The authors say that this reflects the greater genetic variation among Xhosa people.
But statistical geneticist Stephan Ripke at the Broad Institute in Cambridge, Massachusetts, says there could be other explanations for the large effect size, such as differences in the severity of schizophrenia in recruited participants.
The authors of the study say they are planning to extend their research.
Nature 578, 19 (2020)