What is it about?
Major depressive disorder is a leading cause of disability worldwide and can affect people from all communities and backgrounds. Working in close partnership, researchers from the Clinic for Special Children, Columbia University, and Regeneron Genetics Center discovered a rare mutation in a gene called GPR156 that was passed down through the successive generations of Old Order Mennonites to increase individual susceptibility to major depression nearly three-fold. GPR156 is expressed in a deep part of the brain called the medial habenula, known to play a crucial role in behavioral responses to stress.
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Why is it important?
The risk for major depression is partially heritable. Among individuals with major depression, genetic risk is sometimes attributed to the additive effects of multiple genetic changes, each of minor effect. The present work indicates that a single rare genetic variant can have a large effect on depression susceptibility. This finding deepens our understanding of the causes of depression and introduces a new target for its treatment.
Perspectives
Depressive illness is a cause of debilitation and suffering in communities worldwide. The causes of depression are often shrouded in misunderstanding and stigma. Within a conservative agrarian community, we used a family-based genomic approach to trace major depressive illness to a single rare gene variant descending through multiple generations. For members of the Mennonite communities we serve, this finding places depressive illness within a modern biological framework, helps to destigmatize the diagnosis, and opens a path to new antidepressant therapies.
Kevin Strauss
Read the Original
This page is a summary of: A rare variant in
GPR156
associated with depression in a Mennonite pedigree causes habenula hyperactivity and stress sensitivity in mice, Proceedings of the National Academy of Sciences, April 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2404754122.
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