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

BACKGROUND: Genome-wide association studies have identified 14q21.1 as a robust risk locus for major depressive disorder (MDD). However, the underlying mechanism remains elusive. Here, we aim to explore the regulatory function of rs1950834 on leucine-rich repeat and fibronectin type III domain containing 5 (LRFN5) expression in MDD. METHODS: Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-mediated genome knockout and single-base editing were used to determine the effects of rs1950834 on the binding of transcriptional factors and the expression of the target gene LRFN5. Meta-analysis of multiple transcriptomic datasets was performed to clarify the brain region responsible for LRFN5 downregulation in MDD patients. Adeno-associated virus (AAV)-mediated Lrfn5 overexpression or knockdown in the nucleus accumbens (NAc) was used to test their effects on depression-like behaviors and sensitivity to chronic unpredictable mild stress (CUMS) in male mice. Synaptic structure and functions were monitored by synaptic protein expression assay, Golgi staining, and electrophysiological analysis. RESULTS: The risk allele (A) of rs1950834 reduced the binding affinity to RNA polymerase II subunit A (POLR2A) and the transcription factor RAD21 cohesin complex component (RAD21), leading to decreased expression of LRFN5. LRFN5 expression was downregulated specifically in the NAc of MDD patients as compared to healthy controls. Knockdown of Lrfn5 in NAc neurons induced depression-like behaviors and further exacerbated CUMS-induced phenotypes via synaptic damage, but overexpression of Lrfn5 in mouse NAc induced resilience to CUMS. CONCLUSIONS: These findings reveal that the functional risk single nucleotide polymorphism rs1950834 at 14q21.1 regulates LRNN5 expression and function in NAc, providing a novel perspective for molecular diagnosis and targeted interventions of MDD.