Polygenic Risk Score May Predict Stress-Induced Depression

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Depressed woman with head in hands

While there are a number of genes that have been linked to depression, it is broadly accepted that the mental health condition arises from a complex interaction of a person’s molecular make up. But now, researchers have constructed a polygenic risk score (PRS) for major depressive disorder, or MDD-PRS, from widely available consortium and biobank data on the known associations between a person’s risk of depression, and variations throughout a person’s genome.

The study, by a team from the University of Michigan, was conducted on a population of more than 5,200 people in the most stressful year of training for a medical career—the intern year of residency and was published in the journal Nature Human Behaviour.

The doctors for the study were part of the Intern Health Study, which is led by Srijan Sen, M.D., Ph.D., the senior author of the new paper. The Intern Health Study enrolls thousands of new physicians across the U.S. each year who agree to let the research team sample their DNA, and to answer surveys before they begin their intern year of medical training and several times during that intense year of long hours and high demands.

Genetics and stress are known to play a role in depression risk and onset, but until now how there was little information about how they interacted to influence the onset of MDD.

The new research showed that interns who had higher-than-average MDD-PRS scores were slightly more likely to be among the 3% of interns who showed signs of depression before their intern year started. That changed significantly over the course of the year, as by the end of the that group was much more likely to be among the one-third of interns who developed depression.

The research also showed that the group of interns with the lowest MDD-PRS scores were far less likely to show signs of depression throughout their intern year, suggesting that the scoring system could be used to identify those most likely to be resilient despite intense stress.

The research team combined data across millions of sites within the human genomes to construct the MDD-PRS, and looked to see how well a person’s “score” on this tool predicted with their scores on standard surveys of depressive symptoms. They also assessed whether the MDD-PRS worked through known mechanisms to depression, such personal and family history, childhood experience or general temperament.

“Interestingly, we found evidence that the association between MDD-PRS and depression is stronger in the presence of stress and that the additional predictive power of MDD-PRS under stress is largely independent of known risk factors for depression.”  said Sen, the Eisenberg Professorship in Depression and Neurosciences at U-M. “These findings further our understanding of how genomics and stress interact and suggest that further investigation of the genomics of stress response can uncover novel mechanisms that lead to depression.”

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