Yuan Lei, Su Yale, Zhao Jiangqi, Cho Minkyoung, Wang Duo, Yuan Long, Li Mixia, Zheng Dongdong, Piao Hulin, Wang Yong, Zhu Zhicheng, Li Dan, Wang Tiance, Ha Ki-Tae, Park Wonyoung, Liu Kexiang
Department of Cardiovascular Surgery, The Second Hospital of Jilin University, Changchun, China.
Department of Dermatology, The Second Hospital of Jilin University, Changchun, China.
Front Endocrinol (Lausanne). 2025 May 8;16:1578944. doi: 10.3389/fendo.2025.1578944. eCollection 2025.
Increasing evidence suggests that individuals with obesity are at a higher risk of developing depression, and conversely, depression can contribute to the onset of obesity, creating a detrimental cycle. This study aims to investigate the potential shared biological pathways between obesity and depression by examining genetic correlations, identifying common polymorphisms, and conducting cross-trait genetic analyses.
We assessed the genetic correlation between obesity and depression using linkage disequilibrium score regression and high-density lipoprotein levels. We combined two different sources of obesity data using METAL and employed bidirectional Mendelian randomization to determine the causal relationship between obesity and depression. Additionally, we conducted multivariate trait analysis using the MTAG method to improve statistical robustness and identify novel genetic associations. Furthermore, we performed a thorough investigation of independent risk loci using GCTA-COJO, PLACO, MAGMA, POPS, and SMR, integrating different QTL information and methods to further identify risk genes and proteins.
Our analysis revealed genetic correlations and bidirectional positive causal relationships between obesity and depression, highlighting shared risk SNP (rs10789340). We identified RPL31P12, NEGR1, and DCC as common risk genes for obesity and depression. Using the BLISS method, we identified SCG3 and FLRT2 as potential drug targets.
Most of our data sources are from Europe, which may limit the generalization of our findings to other ethnic populations.
This study demonstrates the genetic causal relationship and common risk SNPs, genes, proteins, and pathways between obesity and depression. These findings contribute to a deeper understanding of their pathogenesis and the identification of potential therapeutic targets.
越来越多的证据表明，肥胖个体患抑郁症的风险更高，反之，抑郁症也会促使肥胖的发生，从而形成一个有害的循环。本研究旨在通过检查遗传相关性、识别常见多态性以及进行跨性状遗传分析，来探究肥胖与抑郁症之间潜在的共同生物学途径。
我们使用连锁不平衡评分回归和高密度脂蛋白水平评估肥胖与抑郁症之间的遗传相关性。我们使用METAL合并了两种不同来源的肥胖数据，并采用双向孟德尔随机化来确定肥胖与抑郁症之间的因果关系。此外，我们使用MTAG方法进行多变量性状分析，以提高统计稳健性并识别新的遗传关联。此外，我们使用GCTA - COJO、PLACO、MAGMA、POPS和SMR对独立风险位点进行了全面研究，整合不同的QTL信息和方法以进一步识别风险基因和蛋白质。
我们的分析揭示了肥胖与抑郁症之间的遗传相关性和双向正向因果关系，突出了共同的风险单核苷酸多态性（rs10789340）。我们确定RPL31P12、NEGR1和DCC为肥胖和抑郁症的共同风险基因。使用BLISS方法，我们确定SCG3和FLRT2为潜在的药物靶点。
我们的大多数数据来源来自欧洲，这可能会限制我们的研究结果推广到其他种族人群。
本研究证明了肥胖与抑郁症之间的遗传因果关系以及共同的风险单核苷酸多态性、基因、蛋白质和途径。这些发现有助于更深入地了解它们的发病机制，并识别潜在的治疗靶点。
