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ORIGINAL RESEARCH article

Front. Psychiatry
Sec. Molecular Psychiatry
Volume 16 - 2025 | doi: 10.3389/fpsyt.2025.1414015
This article is part of the Research Topic Molecular Mechanisms in Psychiatry 2023: Bipolar Disorder View all 3 articles

NEK4: Prediction of Available Drug Targets and Common Genetic Linkages in Bipolar Disorder and Major Depressive Disorder

Provisionally accepted
Jing Shen Jing Shen *Chenxu Xiao Chenxu Xiao Yu Feng Yu Feng
  • The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, China

The final, formatted version of the article will be published soon.

    Abstract Background: Bipolar disorder (BD) and major depressive disorder (MDD) are debilitating psychiatric conditions. Pharmacotherapy is vital for management, yet understanding of their genetic underpinnings remains limited. We explored genetic differences in BD and MDD to uncover potential drug targets. Methods: This study utilized genome-wide association studies (GWAS) and summary-data-based Mendelian randomization (SMR) to identify genetic variants and predict drug target genes associated with BD and MDD. GWAS datasets included 41,917 BD cases and 371,549 controls of European ancestry, and 246,363 MDD cases with 561,190 controls. BD data spanned 57 cohorts, integrating DSM-IV/ICD criteria. SMR, with expression quantitative trait loci (eQTL) data from brain tissue and blood, evaluated causal links between variants and gene expression. Two-sample Mendelian randomization (TSMR) assessed protein quantitative trait loci (pQTL) for potential causal associations. Results: SMR identified 41 druggable genes for BD and 45 for MDD, with five and three genes overlapping between brain and blood eQTL datasets, respectively. NEK4 emerged as a shared risk gene for BD and MDD, significantly associated with both diseases (BD: βbrain=0.126, PFDR=0.001; βblood=1.158, PFDR=0.003; MDD: βbrain=0.0316, PFDR=0.022; βblood=0.254, PFDR=0.045). NEK4 also differentiated BD subtypes, associating with type 1 (βbrain=0.123, PFDR=2.97E-05) but not type 2. TSMR revealed four proteins (BMP1, F9, ITIH3, SIGIRR) linked to BD risk, and PSMB4 linked to MDD risk. Conclusion: NEK4 represents a potential drug target and biomarker for BD and MDD, with implications for distinguishing BD subtypes. Our findings highlight druggable genes and proteins associated with BD and MDD, advancing precision medicine in mental health treatment.

    Keywords: Major Depressive Disorder, genetic variants, Drug Targets, Mendelian randomization, NEK4

    Received: 08 Apr 2024; Accepted: 13 Jan 2025.

    Copyright: © 2025 Shen, Xiao and Feng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jing Shen, The Affiliated Jiangsu Shengze Hospital of Nanjing Medical University, Suzhou, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.