2. Academic Validation
  3. The regulatory variant rs1950834 confers the risk of depressive disorder by reducing LRFN5 expression

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

  • BMC Med. 2025 May 30;23(1):316. doi: 10.1186/s12916-025-04141-8.
Di Luan # 1 2,  Yifan Li # 1,  Aini Zhang # 1,  Qingqing Bai # 1,  Te Zhao # 2,  Xi Chen 3,  Xinglun Dang 1,  Junyang Wang 4,  Shaolei Jiang 5,  Yun Sun 1,  Yingjie Zhu 6,  Yan Kong 7,  Xiong-Jian Luo 8,  Zhijun Zhang 9 10
Affiliations

Affiliations

  • 1 Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Research Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease of the Ministry of Education, Southeast University, Nanjing, 210096, China.
  • 2 Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression, Department of Mental Health and Public Health in Faculty of Life and Health Sciences of Shenzhen University of Advanced Technology, The Brain Cognition and Brain Disease Institute of Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
  • 3 The Second Affiliated Hospital of Kunming Medical University, Kunming, 650223, China.
  • 4 Department of Human Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, 450001, China.
  • 5 Key Laboratory of Optical Technology and Instrument for Medicine, Ministry of Education; School of Optical-Electrical Computer Engineering, University of Shanghai for Science and Technology, Shanghai, 200093, China.
  • 6 Shenzhen Key Laboratory of Drug Addiction, Shenzhen Neher Neural Plasticity Laboratory, the Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
  • 7 Department of Biochemistry and Molecular Biology, School of Medicine, Southeast University, Nanjing, Jiangsu, 210009, China. kongyancn@163.com.
  • 8 Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Research Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease of the Ministry of Education, Southeast University, Nanjing, 210096, China. luoxiongjian@seu.edu.cn.
  • 9 Department of Neurology in Affiliated Zhongda Hospital and Jiangsu Provincial Medical Key Discipline, School of Medicine, Research Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease of the Ministry of Education, Southeast University, Nanjing, 210096, China. janemengzhang@vip.163.com.
  • 10 Shenzhen Key Laboratory of Precision Diagnosis and Treatment of Depression, Department of Mental Health and Public Health in Faculty of Life and Health Sciences of Shenzhen University of Advanced Technology, The Brain Cognition and Brain Disease Institute of Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China. janemengzhang@vip.163.com.
  • # Contributed equally.
PMID: 40442660 DOI: 10.1186/s12916-025-04141-8
Abstract

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.

Keywords

LRNF5; Major depressive disorder; Nucleus accumbens; POLR2A; RAD21; rs1950834.

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