Massive genomic study uncovers trove of variants linked to depression


In one of the biggest genome-wide association studies ever conducted, researchers have catalogued 178 gene variants associated with major depression. The study looked at health records from several million people in the hope of developing a genetic test to detect those most at risk of depressive disorders.

Depression is a highly complex disorder with no single cause. A broad array of factors can contribute to depression from social, environmental, and psychological conditions to genetic or physiological factors.

Most recently a 2019 meta-analysis homed in on around 100 genetic variants associated with depression. It was estimated up to 40 percent of a person’s risk for major depression could be attributed to heritable genetic variants.

Now a study led by a team from Yale University has expanded that genetic library of risk factors. Health records were analyzed from 1.2 million subjects, including individuals from the US, UK and Africa. The research reports 178 genetic variants associated with major depressive disorder (MDD).

The next step was to replicate these findings in a separate cohort. Working with genetics company 23andMe the researchers looked at another 1.3 million people and confirmed those genetic markers did indeed correlate with depression.

“What is most heartening is we could replicate our findings in independent data sets,” says Daniel Levey, co-lead author on the new study from the Yale University Department of Psychiatry. “Replication is a hallmark of good science, and this paper points to just how reliable and stable results from GWAS [genome-wide association] studies are becoming.”

Some of the findings validate prior work on the genetic origins of depression, such as the confirmation a variant in the NEGR1 gene plays a role in MDD. This gene is known to influence neural growth and is highly expressed in the hypothalamus. DRD2, a dopamine receptor gene, was also flagged in the new study validating prior research associating it with increased risk of depression and anxiety.

As depression is a deeply heterogeneous condition there will never be a single gene found to be primarily responsible. Like other polygenic conditions, every genetic variant implicated simply adds a tiny bit of extra risk for an individual.

Joel Gelernter, co-senior author on the study, expects there are many more genetic variants to be discovered that can be linked to depression. And, as scientists build this body of knowledge, they will ultimately be able to develop a genetic test to collate all these findings into a polygenic risk score that will help doctors identify those people most susceptible to depression, and other psychiatric disorders.

“…we weren’t surprised by how many variants we found,” adds Gelernter. “And we don’t know how many more there are left to discover — hundreds? Maybe even thousands?”

The new study was published in the journal Nature Neuroscience.

Source: Yale University





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