Depression affects almost 300 million people globally, and is considered a leading cause of disability by the World Health Organization. As with many diseases, studies that have searched for genetic variations associated with depression have been conducted primarily in people of European ancestry, and there is limited data available on genes linked to depression in non-European ancestry groups. Finding such genetic variations can not only help in assessing individuals’ likelihood of developing depression, but potentially provide insight into how to treat the mental illness by pinpointing the genes and proteins that underlie it.

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Researchers have now conducted the largest genomic study to date on depression in a non-European population, focusing on participants with East Asian ancestry. In a study published on September 29 in JAMA Psychiatry, they reveal that not only were a majority of genetic variants associated with depression in European populations not applicable in East Asian ancestral cohorts, but novel indicators emerged in East Asians that had not been discovered in studies on Europeans. The study’s authors caution that the existing knowledge on genetic risk factors for depression is not generalizable to a global population.

“I think it’s a strikingly ambitious effort,” says Andrew Ryder, a cultural-clinical psychologist who specializes in East Asian cultures at Concordia University in Montreal who was unaffiliated with the study. “I see this research as establishing that, even in the hard science aspects of studying humanity, you can’t ignore the social world and the potential influence of culture. . . . It’s too easy for people to assume if we’re doing something scientific, it must be true of people everywhere in the world, rather than building culture into their sense of how their science works.”

Karoline Kuchenbaecker, a genetic epidemiologist at University College London and study coauthor, calls the genetics of depression a “black box” ripe for exploration, especially in nonwhite populations that are understudied. Her colleagues in mainland China and Taiwan had access to East Asian genomic datasets, so “We started out with this idea to put together the largest ever combined dataset for depression in people with East Asian ancestry,” Kuchenbaecker recalls about the origins of the massive project. “At this point, we have really, really large data sets. It’s become affordable to include very large numbers of people in those studies. And that’s what we need in order to find depression-related genes.”

The researchers spent about two years combining data on East Asian participants in various projects conducted in the US, the UK, mainland China, and Taiwan, including the China Kadoorie Biobank, a Taiwanese study on major depressive disorder, 23andMe, the US Women’s Health Initiative, and the UK Biobank. Collaborating institutions identified and tracked down 15,771 participants with depression and 178,777 control participants of East Asian ancestry whose genomic information was in the databases, and collected health information from them via structured clinical reviews, medical records, symptom questionnaires, and surveys. The research group used this consolidated data to define how depression manifested in the study population and identify genetic variants that are more or less frequent in those with the condition.

The scientists had two primary goals: to determine whether genes already linked to depression in studies of mainly European-ancestry populations were associated with the condition in a non-European cohort, and to look for new risk genes in the collected dataset. To address the first, the group assessed 102 known depression risk factors from previous studies, and found that only 11 percent of them were associated with depression in the East Asian cohort.

Conversely, the researchers found five novel genes associated with depression in their dataset. The group was able to link one of the variants to expression levels of the LMX1A gene, which encodes a protein involved in dopamine neuron development. “We’re really keen to follow up and try to understand better how having more or less of this particular gene expressed, which is what our variant does, must be changing to some extent, brain structures and increased susceptibility to depression,” Kuchenbaecker says.

Furthermore, when the scientists compared cardiovascular outcomes of patients with depression in European versus East Asian groups, they saw very different physical conditions associated with the disease. In European studies, clinical depression is correlated with heart problems and a high body mass index (BMI), while among people of East Asian descent, clinical depression correlated with a lower average BMI than controls without the condition. Kuchenbaecker calls these results surprising and wants to dig deeper to verify this inverse relationship between depression and BMI in specific ancestral groups.

Those will be the key genes for depression, the ones that really affect people across the globe. That’s why it’s so important to get this diversity.

— Karoline Kuchenbaecker

To test the influence of environmental and cultural differences on genetic risk factors for depression, the researchers compared people in their dataset living in the US and UK with those living in China and Taiwan. The analysis turned up different genetic variations associated with depression in the two cohorts, supporting the idea that environmental or sociocultural factors affect genes’ influence on risk for depression.

“I do think being able to distinguish the inherently biological differences between populations versus aspects of their country of residence or anything that is sociologically determined is really important,” says Lucia Hindorff, an epidemiologist at the National Human Genome Research Institute who was not involved in the study. To that end, she says, the study’s large sample size, and its inclusion of people living in both the West and Asia, are strengths of the work.

Kuchenbaecker says the team is continuing the research, trying to “be even bigger, and even better” by collecting data from additional non-European ancestry groups.

The authors of the paper emphasize that ancestral diversity in study participants could contribute to more focused development of disease treatments. “I think that those genes that are actually transferable across all groups are the ones that are going to be best for new treatments. . . . Those will be the key genes for depression, the ones that really affect people across the globe. That’s why it’s so important to get this diversity.” Kuchenbaecker says.

Ryder says he is intrigued to see this work go deeper into nuances that Kuchenbaecker touches upon, noting, “East Asian is a culturally complex category that encompasses, at the very minimum, a half-dozen different cultural environments, and depending how you define cultural environments, really could represent hundreds of different communities and ways of living.” Of the current study, he says, “I think it continues on an interesting lineage of thinking about culture and biology together in studying mental health.”