An analysis of multiple genome-wide studies making associations between depression and "risk" locations in the human genome has provided a vivid demonstration that results can vary substantially depending on the ethnicity and even country of origin of those whose genomes are being studied.

Members of the major depression working group of the Psychiatric Genomics Consortium and an international team of researchers that included 10 recipients of BBRF grants and prizes and two BBRF Scientific Council members, Kenneth S. Kendler, M.D., and Murray B. Stein, M.D., MPH, set out to compare results of genome-wide association studies ("GWAS") for depression based on DNA from persons of European ancestry vs. persons of East Asian ancestry. The lead authors of a paper on the team's findings, which appeared in JAMA Psychiatry, were Olga Giannakopoulou, Ph.D., and Karoline Kuchenbaecker, Ph.D., of University College London, UK.

GWAS studies to date have identified 102 specific DNA variants across the genome that correlate with depression risk. The great majority of participants in such studies have been of European descent. The broad question is: can the findings of GWAS studies be generalized across different ancestry groups and different regions of the world? Few studies have been devoted to testing these questions.

In this case, the research team performed a meta-analysis, or a study of multiple prior studies, of GWAS datasets on depression exclusively involving East Asian subjects. Meta-analysis adds significant power to the results of any study considered individually. The team drew upon genome data from 9 cohorts, all comparing the genomes of East Asian individuals with depression vs. East Asian controls with no depression diagnosis.

Altogether, 194,548 genomes formed the basis of the comparisons, which included 15,771 individuals with depression and 178,777 controls. While all were of East Asian descent, the sample included some people residing in East Asian nations, notably China and Taiwan, as well as some people with East Asian ancestors who now live in Western nations. The average age of the participants in the combined sample was 51 years, 63% of whom were female.

The results were dramatic: only 11% of genome locations associated with depression risk in past GWAS studies of people of European ancestry were also found to be risk locations in people of East Asian ancestry. The actual overlap in the two populations is probably greater, Dr. Kuchenbaecker explained, and would likely increase somewhat with a larger sample of individuals of East Asian ancestry.

Still, the differences between individuals of European and East Asian ancestry were striking. Perhaps the most important difference between the two groups was that pertaining to high body mass index (BMI). In people of European ancestry, some of the gene variants linked to higher depression risk are also associated with higher BMI, and vice versa. In people of East Asian ancestry, the oppositive was found: there was an association between variants for higher depression and lower BMI.

In addition to BMI, other correlations from depression studies with European ancestry participants that did not hold up in some East Asian samples were associations with type 2 diabetes and coronary artery disease.

Results of their study, the team said, "supports caution against generalizing findings about depression risk factors across populations, and highlight the need to increase the ancestral and geographic diversity of samples" for illnesses and disorders defined in a consistent way across populations.

"Extending this work to other population groups can yield new biological insights pertinent to specific populations and facilitate improved genetic risk prediction across ancestry groups," they added.

By combining GWAS studies of cohorts of East Asian and European descents, the team identified three novel associations that were not significant, statistically, in either European-based or East Asian-based cohorts considered alone. They also discovered a novel depression association on chromosome 7 in studies conducted with people of East Asian descent that was not detected in depression studies based on U.S. or UK datasets.

Differences in genome-based risk for depression varied not only with participants' geographic location but also how their depression was assessed. This "highlights the heterogeneity underlying depression," the team said. In general, however, this study underlines past findings that the potential genetic effects of each "risk" area identified in any individual are usually small, and on a population basis they are distributed across a very large number of genome variants. This may reflect the varied biological mechanisms that contribute to depression as well as to the complex interplay between genes and environment.

Regarding the latter point, the team noted that non-genetic factors, including cultural differences, may further add to depression's complexity. They cited the example of how obesity is regarded and how that may or may not be associated in certain societies with shame and, thus, possibly, depression in some individuals.

In addition to Dr. Stein and Dr. Kendler, who in addition to being a BBRF Scientific Council member is a 2010 and 2000 BBRF Distinguished Investigator and 1995 BBRF Lieber Prize winner, the team included: Margit Burmeister, Ph.D., 2008 BBRF Distinguished Investigator, 2004 and 2002 Independent Investigator and 1996 and 1993 Young Investigator; Po-Hsiu Kuo, Ph.D., 2017 BBRF Independent Investigator and 2006 Young Investigator; Stephan Ripke, M.D., 2015 BBRF Young Investigator; Erin Dunn, MPH, 2013 BBRF Young Investigator; Andrew M. Mcintosh, M.D., 2010 BBRF Independent Investigator; Eli A. Stahl, Ph.D., 2013 BBRF Young Investigator; Roseann E. Peterson, M.D., 2019 BBRF Young Investigator; and Niamn Mullins, Ph.D., 2020 BBRF Young Investigator.