A team of researchers will lead the largest population study of its kind aimed at learning more about the genetic variations that affect individuals’ risk for depression after receiving a five-year, $8.98 million grant from the National Institute of Mental Health, part of the National Institutes of Health.

The study, “Identifying the Genetic Causes of Depression in a Deeply Phenotyped Population from South Korea,” will focus on deep phenotyping — looking at the full picture of all the clinical features and symptoms and many of the environmental risk factors of the disease or condition — to determine what specific genetic factors could underly major depressive disorder in all the ways it manifests. The study also will create the largest available dataset of genetic information related to major depressive disorder for East Asian individuals, increasing the diversity of genetic discovery efforts.

Kenneth S. Kendler, M.D., professor and eminent scholar at the Virginia Institute for Psychiatric and Behavioral Genetics at Virginia Commonwealth University and a professor in the Department of Psychiatry at the VCU School of Medicine, is one of the three multiple-principal investigators who will be leading the study, which Kendler describes as the “largest deeply phenotyped study of depression yet funded,” alongside researchers at University of California at Los Angeles and Seoul National University Hospital.

The study teams will interview 20,000 women in South Korea — 10,000 with recurrent major depression and 10,000 in the control group — for this project. To keep the sample as homogenous as possible, Kendler said, the study will include women who have had at least two episodes of major depression and who do not have a history of drug or alcohol abuse.

“Depression is a complex condition with many factors, and we need large-scale projects to encompass that complexity to give us a real chance of getting to the underlying causes of major depressive disorder,” Kendler said. “Having a sample of this size allows us to more precisely pinpoint what factors influence how depression manifests.”

With the work this team is doing to understand the causes of major depressive disorder, Kendler is hopeful that, decades in the future, scientists might have a way to treat the biological mechanisms that cause major depression.

“There is certainly hope in the long run, and there already are efforts in that direction to try to develop molecular genetic tests that can indicate with increasing accuracy a person’s vulnerability to major depression,” Kendler said. “This [study] would contribute substantially to that effort.”

The project’s contact multiple-principal investigator, Jonathan Flint, M.D., of the David Geffen School of Medicine at UCLA, has received nearly $9 million for the study, with the bulk of the funds going to Korea for the first four years to support data collection. Kendler’s team will receive more than $535,000 for VCU’s site.

Kendler and his team will facilitate training of researchers, led by Kyoo-Seob Ha, M.D., Ph.D., based at Seoul National University Hospital’s sites in South Korea to assist with teaching a rigorous protocol for interviewing the thousands of study participants around this topic. Flint’s team at UCLA will oversee genotyping efforts and collaborate with the VCU and Korean teams to conduct statistical analyses and disseminate results in scientific papers.

Kendler, one of the world’s most-cited psychiatrists, known for his international population studies of conditions related to mental health, and Flint have worked together for more than two decades on projects of this nature. The number of participants in the study in South Korea is nearly twice the size of a study they completed of depression in a deeply phenotyped population over the past decade in China. That project, centered around the China, Oxford and VCU Experimental Research on Genetic Epidemiology (CONVERGE) consortium, was a study of 12,000 participants — 6,000 with depression — to identify the genetic factors for depression. Through this work, the group identified two genetic markers for major depression, publishing papers on the topic in Nature, JAMA Psychiatry and the American Journal of Psychiatry.

“In CONVERGE, we found some genetic risks that appear to be only important in those individuals that really had had very few environmental risk factors for depression in their life, while other kinds of genetic factors were more important in women developing depression that had experienced quite a lot of adversity — either in childhood with physical or sexual abuse or in adulthood with traumatic life events,” Kendler said. “We’re trying to look at how stressful life events relate to the development [of depression] over time. It really is about the etiology of major depression using these powerful molecular tools as a way into that problem.”

Depression affects 10% to 15% of the world’s population, Kendler said, and is a leading cause of disability worldwide, according to the World Health Organization. To determine the causes of this disease, Kendler and his team are trying to understand the genetic and environmental risks as well as interactions among them.

The research team will ask participants detailed questions about their symptoms of depression, such as changes in mood, sleep or appetite, incidence of anxiety or panic, and history of stressors or abuse, and how often they’ve had them, Kendler said.

“We are digging deeply into trying to get, not just the ‘yes’ [or] ‘no,’” around whether someone has experienced major depression, Kendler said, “but much of the deep characteristics of the complexity of this syndrome of major depression.”

Not only is the project an opportunity to contribute to scientists’ knowledge about the causes of major depression, which will help researchers develop more effective tests and treatments for the disease, but it is also an opportunity to diversify the picture of genetics research that exists on risk factors for depression in individuals who are not of European ancestry. A 2019 paper published in Cell by Roseann E. Peterson, Ph.D., a VCU co-investigator who will focus on statistical genetic analysis for the latest project in South Korea, found the need for greater diversity in genomewide association studies to find the causes and possible treatments for diseases.

“Without global representation in genetic studies, precision medicine efforts will be limited because we are not studying the full spectrum of human genetic diversity. It is both a scientific and ethical imperative that we broaden the populations studied in order to improve the understanding of diseases in all populations,” said Peterson, an assistant professor of psychiatry at VCU’s Virginia Institute for Psychiatric and Behavioral Genetics. “A study of this size will help us gather some of that data to identify genetic factors for depression and can help us determine the causes of the disease to develop appropriate prevention and treatments down the line.”

Along with other population-based research projects already underway at VCU, this new investigation spearheaded by Flint, Ha and Kendler on major depression in South Korea will increase the knowledge available about the risks for disease in individuals of East Asian descent, an important step toward making medicine more precise, said Peter Buckley, M.D., dean of VCU School of Medicine.

“This project is one of several ways our researchers are addressing the gaps that need to be filled to make precision medicine truly possible, helping us address the unique needs of all patients, regardless of their ancestral background,” Buckley said. “Dr. Kendler and Dr. Peterson’s study will provide crucial data needed to identify risks associated with major depressive disorder and hopefully lead to improvements in diagnosis and treatment for people around the world.”