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The regulatory variant rs1950834 confers the risk of depressive disorder by reducing LRFN5 expression

Summary

Researchers identified a genetic variant (rs1950834) that increases depression risk by reducing production of LRFN5, a protein important for brain connections. They found this variant affects how brain cells in a region called the nucleus accumbens produce LRFN5. When LRFN5 levels are low, mice become more depressed and sensitive to stress, but boosting LRFN5 protects against depression. This discovery could lead to new ways to diagnose and treat depression.

Background

Genome-wide association studies have identified 14q21.1 as a robust risk locus for major depressive disorder (MDD), but the underlying molecular mechanisms remain unclear. The rs1950834 variant, located in the promoter region of LRFN5, has been associated with depression risk. LRFN5 is a synaptic adhesion protein involved in synaptic development and function.

Objective

To explore the regulatory function of the rs1950834 variant on LRFN5 expression and determine its role in major depressive disorder pathogenesis. The study aimed to identify which brain regions and neuronal cell types are affected and to validate the functional consequences of LRFN5 dysregulation.

Results

The risk allele (A) of rs1950834 reduced binding affinity to transcription factors POLR2A and RAD21, decreasing LRFN5 expression. LRFN5 was specifically downregulated in the NAc of MDD patients. Lrfn5 knockdown in NAc neurons induced depression-like behaviors and exacerbated CUMS-induced phenotypes via synaptic damage, while overexpression induced resilience to CUMS.

Conclusion

The rs1950834 variant functions as a regulatory risk SNP that reduces LRFN5 expression specifically in NAc neurons through altered transcription factor binding. NAc neuron-derived LRFN5 plays a protective role against depression, providing novel perspectives for molecular diagnosis and targeted interventions in MDD.
  • Published in:BMC Medicine,
  • Study Type:Functional Genomics Study,
  • Source: 40442660
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