Genetic Risk for Depression Impacts Neural Responses to Rewards and Setbacks

Novel imaging research indicates that young adults with a higher genetic risk for depression showed less brain activity in several areas when responding to rewards and punishments. The study also uncovered notable differences between men and women. The findings from this new study in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier, highlight potential early indicators for depression before clinical symptoms fully manifest.

Depression is one of the most common mental health conditions, and many people with depression have trouble processing rewards and punishments. It is known that genetics plays a role in depression, but it is not yet clear how genetic risk might affect the brain’s response to positive and negative experiences. The researchers of the current study explored this connection in young adults before symptoms of depression fully developed.

In one of the first studies to show how genetic risk for depression might affect how the brain responds to good and bad outcomes in everyday decision-making, researchers explored how neural markers of reward and punishment processing reflect the overall genetic risks for depression, whether these markers are distinct from those associated with depression severity, and whether men and women show differences in these genetically informed neural markers.

"The study's focus on individuals who are not yet diagnosed with depression paves the way for a better understanding of how genetic predisposition interacts with brain function in the context of reward and punishment, opening up new avenues for early detection and targeted therapies for depression," comments Editor-in-Chief of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging Cameron S. Carter, MD, University of California Irvine.

Researchers evaluated functional MRI brain scans and genotyping data from nearly 900 healthy twins or siblings (ages 22-35) in the Human Connectome Project (HCP) while they played a gambling game that involved winning or losing money. They looked at how the participants’ brains responded during wins and losses, and how that related to their genetic risk for depression.

Lead investigator Chiang-Shan R. Li, MD, PhD, Department of Psychiatry and Department of Neuroscience, Yale University School of Medicine, and Inter-department Neuroscience Program and Wu Tsai Institute, Yale University, reports, “We found that individuals with higher genetic risk for depression showed less activity in brain areas linked to attention and decision-making like the frontal, parietal, and occipital cortical regions of the brain. One area, the posterior cingulate cortex, was strongly associated with punishment but not reward processing. This potential punishment-specific region opens up interesting new questions. We also observed sex-dependent neural responses that suggest potentially sex-specific neurobiological pathways linking genetic risk to depression.”

Lead author of the article Yu Chen, PhD, Department of Psychiatry, Yale University School of Medicine, concludes, “This research shows that genetic risk for depression can quietly influence how the brain reacts to everyday rewards and setbacks—even before someone feels depressed. These early brain markers could help us detect who is at risk and find better ways to intervene before symptoms appear. The gender differences identified make this work exceptionally timely, as the field moves toward more personalized mental healthcare.”

Notes for editors

The article is "Polygenic Risks for Depression and Neural Responses to Reward and Punishment in Young Adults," by Yu Chen, Huey-Ting Li, Xingguang Luo, Guangfei Li, Jaime S. Ide, and Chiang-Shan R. Li (https://doi.org/10.1016/j.bpsc.2025.05.008). It appears online in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, published by Elsevier.

The article is openly available athttps://www.biologicalpsychiatrycnni.org/article/S2451-9022(25)00167-3/fulltext.

Copies of this paper are also available to credentialed journalists upon request; please contact Rhiannon Bugno at [email protected]. Journalists wishing to interview the study’s authors should contact Yu Chen, PhD, at [email protected].

The authors’ affiliations and disclosures of financial and conflicts of interest are available in the article.

Cameron S. Carter, MD, is Chair of the Department of Psychiatry & Human Behavior at the University of California, Irvine School of Medicine. His disclosures of financial and conflicts of interest are available here.

This study is supported by NIH grants AG072893 and DA051922.

About Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

Biological Psychiatry: Cognitive Neuroscience and Neuroimaging is an official journal of the Society of Biological Psychiatry, whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal focuses on studies using the tools and constructs of cognitive neuroscience, including the full range of non-invasive neuroimaging and human extra- and intracranial physiological recording methodologies. It publishes both basic and clinical studies, including those that incorporate genetic data, pharmacological challenges, and computational modeling approaches. The 2024 Journal Impact Factor^TM score, from Clarivate, for Biological Psychiatry: Cognitive Neuroscience and Neuroimaging is 4.8.www.sobp.org/bpcnni

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