Most genome studies conducted to date that have aimed to identify DNA variations associated with various psychiatric illnesses have depended upon samples drawn from populations composed mostly of people of European ancestry.

An international team that includes a number of past and current BBRF grant recipients recently reported in Nature Genetics on their latest effort to determine the degree to which results obtained from existing studies are applicable to people of non-European ancestry.  The team conducted a large multi-ancestry genome-wide association study (GWAS) for major depression that incorporated and assessed genome data from nearly one million people: 88,316 people of non-European ancestry diagnosed with major depression, and 902,757 controls.  

The results offer powerful evidence that increasing the ancestral and geographical diversity of populations sampled in genetic studies may be particularly important to ensure discovery of “core genes” linked with risk for specific illnesses.  In the current study, many new genomic “loci,” or risk locations, were discovered in the combined non-European sample, as well as many genes never before linked with major depression. The latter can shed new light on the biology of depression, including risk and causation factors, as well as potential new targets for therapy.

Led by Karoline Kuchenbaecker, Ph.D., of University College London, and including BBRF grantees including 2019 BBRF Young Investigator Daniel F. Levey. Ph.D., and BBRF Scientific Council members Murray B. Stein, M.D. MPH, and Kenneth S. Kendler, M.D., the research team analyzed samples of major depression patients and matched controls, 36% of whom were of African descent, 26% East Asian, 6% South Asian, and 32% Hispanic/Latin American. The sample was diverse in terms of participants’ ancestry, but not necessarily current geographical location. Many within the 21 separate cohorts of participants that made up the new sample resided in North America and Europe when they contributed their DNA samples.

Previous genetic research using mostly European cohorts has revealed the extremely complex genetic architecture of depression. That is a finding that will not change with more diverse sampling.  Genome variations are only one source of risk for the illness; a plethora of environmental factors can potentially be involved, depending on the individual. Still, the genetic risk profile, to the extent it is currently understood, suggests that the genetic portion of total risk is conferred across the vast human population by many different DNA variations—hundreds have so far been identified—each of which contributes a small increment of any individual’s depression risk. The largest GWAS to date, based mostly on people of European ancestry, found 233 DNA variations that corresponded with increased risk for depression.

A study published several years ago by many of the same researchers involved in the newly reported study found that some previously identified risk locations based on analysis of European-descended participants were not transferable to individuals of East Asian ancestry.  While suggestive, the study was comparatively small in terms of sample size—which directly corresponds with the statistical power of GWAS results—and so the team undertook to collect a larger and much more diverse sample, leading to the current multi-ancestral study.   

This first-ever large-scale multi-ancestry GWAS for major depression found 53 genome locations, or loci, associated with risk that had never been previously identified. Using a technique called fine mapping and a type of study called TWAS (transcriptome-wide association study) that analyzes gene expression, the team identified 205 novel genes that are plausibly affected in the 53 novel risk loci. These findings provide clues that are likely to increase the current biological understanding of depression’s causation.  Researchers work back from associated genes to the biological processes that the genes are involved in, in the brain, the immune system, etc.  These in turn become the focus of new experiments, seeking to validate or disprove causal linkages.  

In addition to enabling the team to find new risk locations and potential risk genes, the diversity of the non-European sample in combination with the large sample size enabled the team to compare the understanding of causal genetic factors in major depression across ancestry groups.  The team developed a method called power-adjusted transferability, or PAT, to estimate the degree to which genetic risk factors identified in one ancestry group were likely to also pertain in other groups.  

The numbers were remarkable: in a set of 206 risk factors identified in GWAS of people of European ancestry, the “transferability” of these factors was 27% in the African ancestry samples analyzed in the current study; 29% in the East Asian and South Asian ancestry samples; and 63% in the Hispanic/Latin American ancestry sample. (The much higher figure in the Hispanic/Latin American sample may reflect that many of these participants had a considerable portion of European ancestry.)

In addition to showing how much more there is to understand about genetic factors involved in depression (and other illnesses) when diverse populations are included in the analysis, the new study “represents an evidence-based starting point for further follow up” on many research fronts, the team said. One of many possible subjects is to further explore whether it is true that with regard to metabolic traits and body-mass index scores, East Asian individuals have the opposite risk relationship compared with people of European ancestry.  In the latter, those traits are positively correlated with major depression. In East Asian individuals, lower BMI and lower metabolic risk correlates with higher depression risk—a conundrum.

In addition to its value for advancing biological understanding of depression, “increasing diversity in genetic research is also important to ensure equitable health benefits,” the team noted. “In the U.S., differences in presentation of major depression across ethnic groups can impact on the likelihood of diagnosis. Genetics optimized for European ancestry would primarily benefit that group of patients and could therefore further widen the disparities in diagnosis and treatment between groups.”

In addition to Drs. Levey, Stein, and Kendler (the latter is also a 2010 and 2000 BBRF Distinguished Investigator and 1995 Lieber Prize winner), the team also included: Erin C. Dunn, ScD, MPH, 2016 Klerman Prize honorable mention and 2013 BBRF Young Investigator; Renato Polimanti, Ph.D., 2015 BBRF Young Investigator; Andrew M. McIntosh, M.D., 2010 BBRF Independent Investigator; Stephan Ripke, M.D., Ph.D., 2015 BBRF Young Investigator; Jonathan R.I. Coleman, Ph.D., 2021 BBRF Young Investigator; Margit Burmeister, Ph.D., 2008 BBRF Distinguished Investigator, 2004 and 2002 Independent Investigator and 1996 and 1993 Young Investigator; Roseann E. Peterson, Ph.D., 2019 BBRF Young Investigator; Po-Hsiu Kuo, Ph.D., 2017 BBRF Independent Investigator, 2006 Young Investigator; Megan L. Campbell Ph.D., 2008 BBRF Young Investigator; and Dan J. Stein, Ph.D., 1991 BBRF Young Investigator.