A Schizophrenia Study in Africa is Boosting Equity in Global Genetics Research
The largest psychiatric genetics study ever done in Africa is increasing the diversity of data on mental illness, training a new generation of geneticists, and chipping away at the genetic underpinnings of schizophrenia and bipolar disorder.
It was not quite noon yet, but Mirembe had already had a long day. She had come to Butabika Hospital in Uganda early that morning, first to see a nurse and a doctor, and now stepped into a warm, sparsely-furnished office. Sitting down across the table from a research assistant, she wondered how long she was going to be there. But she was curious. The nurse had told her a little about a research study on mental illness and that she was eligible to participate if she agreed to sign up. She was full of questions.
Mirembe (not her real name) is one of tens of thousands of outpatients seen every year at Butabika, the national mental health hospital for all of Uganda, located on a hill on the outskirts of the capital city, Kampala. Over the next two hours, she would learn in detail what the research study was about and decide whether to participate. If she said yes, she would then answer more than 150 questions about her health, provide some of her saliva for DNA, and become one of more than 19,000 people across four African countries who, over the last two years, have signed on to help scientists in Africa, the United States, and beyond better understand the genetic roots of schizophrenia, bipolar disorder, and other psychiatric illnesses.
That effort, the Neuropsychiatric Genetics of African Populations-Psychosis (or NeuroGAP-Psychosis) project, is the largest study of psychiatric genetics ever conducted in Africa. Bringing together scientists and doctors from Uganda, Kenya, Ethiopia, South Africa, and the United States, the four-year-long project seeks to engage 35,000 Africans in a quest to gain a deeper biological understanding of schizophrenia and bipolar disorder across a diversity of populations.
Current genetic data on mental illness are mostly from people of European ancestry, and NeuroGAP-Psychosis aims to change that, by ensuring that African science and people are represented in the search for genetic markers for these diseases.
"The world is moving towards precision medicines," said Dr. Dickens Akena, a psychiatrist and the NeuroGAP-Psychosis lead investigator in Uganda, and a psychiatry lecturer at Makerere University in Kampala. "If we're going to make medications or diagnostics that are tailored towards certain genetic variations, then we need to include populations from Africa in the genetic data. If we don't do that, the African continent and its inhabitants will be left behind."
Now two years into recruitment, NeuroGAP-Psychosis researchers are more than half-way towards reaching that 35,000-participant goal. Though the team paused the project for a few months in 2020 as SARS-CoV-2 swept the globe, they have started enrolling participants again, and have begun analyzing some of the DNA and data collected before the pandemic struck.
Once the study reaches the 35,000 participant mark, NeuroGAP-Psychosis team members will run a genome-wide association study (GWAS). They’ll use statistical tests that compare the genetic data from people with schizophrenia or bipolar disorder and from healthy controls to search for genetic signatures and patterns that are strongly associated with these diseases.
The project is also helping the pan-African genetics and psychiatric research community flourish through education, training, and investment in research infrastructure. While genomics research capacity is growing in some parts of the continent, NeuroGAP-Psychosis aims to boost this capacity across more regions of Africa.
"I hope the work we're doing will contribute, even a little bit, to the discovery of new diagnostic techniques and new treatments for illnesses that cause such a huge burden of suffering, and leave behind infrastructure that will enable Africans to participate fully in the global search for answers in mental health," said Professor Lukoye Atwoli, a professor of psychiatry and dean of the Aga Khan University Medical College, East Africa, in Nairobi, Kenya, and principal investigator of the NeuroGAP Psychosis study site at Moi University and Moi Teaching and Referral Hospital (MTRH) in Eldoret, Kenya.
Schizophrenia, bipolar disorder, and other psychiatric disorders cause immense suffering worldwide, accounting for a quarter of the global burden of disease. Genetics plays a major role in these diseases, but scientists are still learning which genes are involved, the cellular circuits they affect, and how those circuits affect the brain.
Learning more about this biology requires a great deal of patient involvement and genetic data. The international Psychiatric Genomics Consortium (PGC), for example, has screened the DNA of more than 150,000 people, thus far finding more than 250 locations (or loci) in the human genome with ties to schizophrenia.
But the data lack diversity. A 2019 review found that across all human genetics studies, more than 78 percent of the people represented were of European ancestry, 10 percent were from Asian populations, and a scant 2 percent were from Africa. This doesn't come close to reflecting the world's population, where 60 percent are of Asian descent and nearly 17 percent African; people of European ancestry account for only 10.
While genetics work has been done in Africa, most efforts have been on a smaller scale than other regions and few have focused on mental illness. The 1000 Genomes Project, which set out to systematically catalogue human genetic diversity, recruited about 1,300 people from five ancestries in western and eastern Africa. The African Genome Variation Project (AGVP) worked with about 1,500 people from 16 ancestral groups in six countries. (By comparison, about half a million Britons participated in the United Kingdom's UK Biobank effort.) And for more than a decade, the Human Health & Heredity in Africa (H3Africa) project has supported teams in 12 countries studying the genetics of various chronic and infectious diseases, but has focused less on psychiatry.
"Overall, there's not a lot of work that has been done regarding the genetics of anything in the African population, let alone mental illness," Akena said.
Atwoli, Akena, and their colleagues worry that unless this changes, treatments and diagnostics developed using genetic data will leave patients of African and other ancestries behind. For instance, geneticists already recognize that polygenic scores — which measure the contributions of thousands of genes to disease risk — currently do a relatively poor job of predicting disease risk for people of non-European ancestry, largely because the scores were built using data from European populations.
"The roots of the human race are found on the African continent," Atwoli said. "If you do not look closely at the roots, then you have a picture of only a section of humanity."
Geneticists and psychiatrists from Africa and the United States realized that a far bigger effort was needed to more fully study the genetics of mental illness in Africa. Africans as a population harbor more genetic diversity than any other on Earth, and studying their DNA and health data could reveal new insight into the genetic causes of psychosis.
Steven Hyman, co-director of the Stanley Center for Psychiatric Research at the Broad Institute, and associate member Karestan Koenen, a professor of psychiatric epidemiology at the Harvard T.H. Chan School of Public Health, first envisioned NeuroGAP-Psychosis as a way to help meet those goals.
“NeuroGAP-Psychosis’s long-term aim is to eliminate the diversity gap in genetics, which is not just about equity but is critical for scientific advance," Koenen explained. "Africa has the most genetic diversity globally, and if we don’t study African populations we risk missing novel genetic information."
The roots of the project — one of several in the Stanley Global Neuropsychiatric Genetics Initiative (aka Stanley Global) — lie in long-standing relationships and collaborations among many of its lead scientists. Researchers, doctors, and bioethicists from the institutions in the project spent two years figuring out the details of the project and getting approval from the African universities’ institutional review boards to ensure that all DNA samples, data, and results would be openly shared with all collaborators, and that all samples and data from participants would remain in Africa, under the control of African universities.
"This is groundbreaking research," Akena said. "We could be the first people to have 35,000 DNA samples in Africa. That's huge."
Study leaders hope their work will help ensure that future biomarker-based diagnostic tools and therapeutics will work for as many people around the world as possible.
"When we understand more about the genetics of psychosis in Africa, and when new interventions are developed, we won't be wondering, as we have always wondered, whether our patients will benefit," said Dr. Edith Kwobah, a NeuroGAP-Psychosis co-investigator and psychiatrist at MTRH. "We can say with more confidence that we were represented in the underlying research. It's good for the African continent as a whole."
Mirembe arrived at Butabika Hospital early that morning along with dozens of others — some on foot or by car, many on the back of a boda-boda (motorcycle taxis common throughout eastern Africa). After checking in, she and the other patients took seats in a large, open-air shelter next to the hospital's outpatient building, waiting to be called.
At this outpatient clinic — one of more than 30 other NeuroGAP-Psychosis clinical sites in four countries — nurses help recruit patients for the study once the patients have received their care. A nurse had approached Mirembe because she met the study’s criteria — age 18 or over, fluent in English or the predominant local language, diagnosed with psychosis, and not suffering an active psychotic episode. Control participants, who don’t have a psychosis diagnosis, come to the study through other paths, but always in a healthcare setting.
After Mirembe expressed interest in learning about the study, she sat down with a NeuroGAP-Psychosis research assistant (RA) named Julius Okura. Okura is one of more than 40 RAs who interviews participants, guides them through the informed consent process, and collects saliva samples for DNA analysis. The RAs come from a variety of careers and backgrounds, such as psychology or nursing. Okura is an IT specialist by training and initially joined the team as an administrative assistant. He later pitched in with project management before study leaders asked him to help recruit patients.
After making sure Mirembe was comfortable, Okura began carefully explaining to her the purpose of the research, what her data and DNA would be used for, and that the data would be stripped of any identifying information. As he read the entire five-page study description and consent form out loud, Okura paused frequently to see if Mirembe had any questions, and made it clear that she could stop or decline to participate in the study at any point during the conversation. [N.B. Mirembe gave permission for members of the Broad communications team to be present during her enrollment interview.]
To ensure she understood the nature of the study, Okura gave Mirembe a 10-question test called the UBACC (short for University of California, San Diego Brief Assessment of Capacity to Consent).
"It lets us assess with rigor that the person we're talking to understands the study, understands what they’re consenting to, and can make an informed decision about participating," Akena said.
After Mirembe successfully completed the UBACC and signed the consent form, Okura pulled out an orange-capped saliva collection kit, carefully explaining how to use it.
Over the course of two hours, Okura asked Mirembe several questions about her background, demographics, and medical and psychological history. That rich trove of information, when aggregated with similar data from all of the participants, will form the backbone of NeuroGAP-Psychosis's genetic analysis.
Once the project reaches its goal of recruiting 35,000 participants — more than 17,000 patients and 17,000 controls — the study should have the statistical power to pick up signals in the data pointing to genetic clues related to psychosis.
But recruiting people for the study isn’t easy.
"Some of the constructs we use in genetics have never been translated into an African language,” Akena explained. “For example, in Acholi, my home language, there isn't a word for genetics. There isn't a word for gene, or for cell, or for DNA. So sometimes we have to go to extra lengths to be able to explain to participants what this is all about."
Cultural beliefs are also a factor. All of the DNA collected for the study comes from saliva, and “saliva” can carry different significance in different societies. “It's considered part of the body, and people are concerned about what will be done with it," said Kwobah. “And in general, genetic research is not yet fully acceptable in many cultures here."
The RAs deal with these challenges by taking extra time — sometimes as long as one hour — to ensure that participants understand key biological concepts, and by being transparent about how participants’ samples and data will be secured, stored, and used. Okura said that he and the other RAs also carefully explain why patients don’t get their results. "But we also remind them that people like them in the future will benefit from the fact that they took part in this research."
Any biomedical study in Africa comes with unique ethical challenges, stemming from the continent's history of exploitation by western and colonial nations and high levels of economic disparity. For NeuroGAP-Psychosis, the challenges are even greater.
"We're dealing with a very vulnerable population, and with unequal power relations between the researchers and the researched," said Professor Violet Naanyu, a bioethicist at Moi University and a member of the Global Initiative in Neuropsychiatric GenEthics (NeuroGenE), an initiative based at the University of Oxford that works in partnership with Stanley Global. "We also face high levels of poverty, which can increase reliance and dependency, and of illiteracy, which can leave people vulnerable to abuse."
Naanyu and other bioethicists are part of the African Ethics Working Group, which was convened by NeuroGenE, and has been advising NeuroGAP-Psychosis leaders since the earliest days of the project to help them navigate the study's ethical complexities.
Despite the challenges, the study is on track to reach its enrollment goal by the time this phase of the study is scheduled to end, in 2022. "NeuroGAP has grown faster than we ever envisaged," Atwoli said.
Peering out his office window at the darkening gray sky, Joseph Kyebuzibwa, the NeuroGAP-Psychosis project manager in Uganda, grew worried. It was shortly after noon and the rain had just started falling — the kind of drenching storm that blows across southern Uganda regularly in late autumn, flooding roads and bringing Kampala's already epic traffic to a standstill. Adjusting his glasses, he looked at the box of saliva kits on his desk: more than 300 samples that were to be processed that afternoon at the lab at Makerere University, on the other side of the city. "I hope this passes soon," he said, "but we might be here for a couple of hours."
Eventually the storm blew out, and Kyebuzibwa raced across the city, trying to get ahead of other drivers returning to the streets. Walking quickly across the Makerere campus and into one of the university's health science buildings, he headed up to a fourth floor lab run by H3Africa — the Integrated Biorepository of H3Africa Uganda (IBRH3AU) — working with NeuroGAP-Psychosis to extract and bank DNA from samples from Ugandan participants. Handing the box over to the laboratory staff, Kyebuzibwa looked on as they started logging the samples into their tracking system and kicked off a 24-hour process for extracting and storing the DNA.
Keeping African DNA samples on African soil has been a key part of the NeuroGAP-Psychosis from the start.
"In past collaborations, people have simply come, taken the samples, shipped them out, and we haven't seen them again," Akena said. "We haven't seen them for data analysis, for example. We haven't seen them when it comes time to publish. You find maybe one or two African colleagues on a paper's author list, and they're in the middle or towards the end."
In NeuroGAP-Psychosis, every saliva sample goes to a local laboratory — IBRH3AU in Kampala, for example, or a lab run in Eldoret by the North American/Kenyan AMPATH partnership. Technicians in these labs extract DNA from a small amount of the saliva sample; the rest is saved and stored at these labs for future studies.
A small portion of the extracted DNA is sent to the Broad Institute's Genomics Platform for processing and analysis, to allow the NeuroGAP-Psychosis team to tap into the institute's genomic and computational resources, which are still hard to come by in the project's participating countries at the scale needed for this study.
The remainder of each participant's DNA, and more than two-thirds of each participant's donated saliva, stays at the local laboratory under the governance of the institution that collected it.
"One of the key things with this project is that we keep most of the DNA here," Akena said. "We have full control of what remains here. You don't see that in other collaborations."
All of the genetic, health, and survey data are stripped of identifiers, stored securely in the cloud, and are accessible by team members on both sides of the Atlantic. Consent forms and any other material containing a participant's identity stay in that person’s home country.
NeuroGAP-Psychosis team members will use the de-identified data from the 35,000 participants to run a GWAS for genetic markers for schizophrenia or bipolar disorder. The data and results will be shared globally in secured databases.
In the small NeuroGAP-Psychosis office in Eldoret, Kenya, four RAs waited as Anne Stevenson, the Stanley Center's NeuroGAP-Psychosis program director, passed around a handout. Stevenson had been in Eldoret for four days on a site visit to MTRH, one of several that she and other project staffers make to all of the study sites every year, removing roadblocks and helping make sure the project runs smoothly.
She was excited to share with the RAs the results of the first genetic analysis of any NeuroGAP-Psychosis data.
"The recruitment teams have put in an incredible amount of work to get us to where we are," she said. "Engaging with them so they can see the results that have come out of what they do day-to-day — to me that's one of the greatest parts of this project so far."
Stevenson’s handout described a quality-control study by Broad geneticists, comparing ancestry-related genetic markers in samples from each of the project’s five main sites with similar markers cataloged by the 1000 Genomes and African Genome Variation projects.
"If participants from Eldoret, for example, report being part of a particular ancestral group, and we see the same ancestry markers in our data that other studies identified for that group, then our samples and processes are working," Stevenson explained.
The samples from all of the sites passed the quality-control tests with flying colors, with the data largely reflecting the 1000 Genomes and AGVP markers for their respective regions. It suggests that the study’s protocols are working well and the researchers were collecting good-quality samples and data for the GWAS phase of the project.
"Seeing these results, it feels really good," said Eunice Jeptanui, one of the MTRH RAs. "We can happily say that we're contributing to science. And we're looking forward to seeing more results in the future."
One of NeuroGAP-Psychosis's greatest impacts could happen at a subtle level, namely, by helping change perceptions of mental illness, one person at a time, starting with project staff members like Stella Gichuru.
"At first, I used to be scared of the patients," Gichuru admitted. "People see patients with mental illness as amerogwa, as bewitched. I used to think they were violent, and I would look for an interview room that had two doors, so that if they became violent, I could run out."
Gichuru's earlier fears reflect a stigma that runs deep in Kenya (and in Africa and beyond) and that has, in some ways, become part of health care policy in Kenya and elsewhere in Africa, said Kwobah, the MTRH co-investigator.
"People understand illness as a fever, a swelling, a wound. The challenge has been that governments and health ministries have been more worried about HIV, cancer, and other conditions that directly cause physical illness and death, rather than mental illness,” Kwobah said. "But I think things are changing now."
Other NeuroGAP-Psychosis team members agree: they hope the project will help guide mental health care in Africa in new directions, by showing that mental illness is a real disease that should be diagnosed and treated like any other disease.
"There are no biomarker-based tests for mental illness, and people wonder how we can treat patients if there are no tests,” said WDC Kinyanjui, the head of the mental health department at Moi University's School of Medicine. "But if we're able to say that there is a biomarker, a test, as a result of genetic study of these diseases, people will start understanding that these are actually diseases. We'll be able to undercut the stigma."
Atwoli said the project could also transform how science and mental health research are done in Africa, and help bring equity to the forefront of genetics research globally.
"It is time for the global scientific community to start thinking about equity, and not just collect data in small areas of the world and think that this represents the global population,” Atwoli said. “I think NeuroGAP should be that beacon that reminds the global scientific community that equity is also a consideration in research."
Gichuru said the project has already had a major impact on her. "I've come to understand that patients are people just like us. And if I understand this, I think my community will understand; if I understand, my village will understand, because I can teach them."
This story and the videos are based on a site visit to Kenya and Uganda in November 2019.