Scientists link DNA variations to major depression for the first time

For the first time, researchers have identified two genetic variants that predispose humans to major depressive disorder, according to a study published in Nature today. The finding is specific to Han Chinese women, so this isn’t a universally relevant piece of information. Still, this discovery could help researchers get a handle on the biology of depression — in addition to enabling the identification of new drug targets.

“We are at the beginning of a trail that can lead us to clarifying the underlying biology of depression, which can then open up treatment possibilities that have hitherto been impossible,” says Kenneth Kendler, a psychiatrist and human geneticist at the Virginia Commonwealth University and a co-author of the study.

Major depression is common in the US. In 2012, roughly 7 percent of US adults — that’s about 16 million people — experienced at least one major depressive episode. But despite their best efforts, researchers have had a very hard time finding genetic markers that can be linked to depression. That’s unfortunate; finding a genetic link could lead to more effective drugs, preventing a lot of emotional pain in the process.

In the study, researchers sequenced the genomes of over 5,000 Han Chinese women with recurrent major depressive disorder. This helped them identify the two genetic variants — versions of genes that are both located on chromosome 10 — that appear to be linked to depression. Then, they verified their findings in a second set of Han Chinese women.

The finding doesn’t mean that these two genetic variants are the sole cause of the disorder, however. They are actually responsible for less than 1 percent of a person’s chance of developing major depression. Their effect is small but nevertheless significant — and that’s a scientific first.

When the researchers tried to replicate their findings in a large European population, however, the experiment was unsuccessful. One potential explanation for this result is that the part of the genome that “hosts” these variants differs substantially in European versus East Asian populations, Kendler says. Indeed, the two variants are found in about 50 percent and 25 percent of Han women, respectively, but they’re only present in approximately 8 percent and 3 percent of the European population. Thus, comparing across ethnicities might not be possible.

“This is an important study because it convincingly identifies DNA variations linked to depression for the first time,” says Jordan Smoller, a psychiatrist at Harvard University who didn’t work on the study. “It provides clues to the underlying biology of depression — and perhaps new targets for developing treatments.” Others remains skeptical, however.

“Fundamentally, I have difficulty deciding to what extent I believe the findings at all,” says David Cutler, a human geneticist at Emory University who didn’t work on the study. The link between the two genetic variants and major depressive disorder is “at best borderline significant in the initial study,” he says, meaning that the tests show a very weak effect. And although the replication study helps validate some of the conclusions, it only examined about 12 genes — as opposed to the whole genome — which means that it can’t be used to verify the entire initial experiment.

That said, if the findings are correct, they highlight an interesting dynamic. This specific population of Han women may have helped the researchers identify two genetic variants that, although rare, may still exact a significant — albeit very small — overall effect in Europeans, Cutler says.

For Kendler, the rarity of these variants means that a lot more work will need to be done to clarify their role. Studies in men and other populations will also have to take place. But focusing on those two variants could “ultimately clarify a mechanism that makes people vulnerable, and other people relatively invulnerable, to depression,” he says.

In short, the finding may be the string that will lead researchers back to an quilt’s worth of depression biology.

“Right now, all of the commonly used antidepressants are based on biological hypotheses that are more than 50 years old,” Smoller says. “By opening a window onto specific genes related to the development of depression, genetic research may reveal new biological pathways that can lead to more effective and targeted treatment options.”