研究重度抑郁症和中枢性肥胖之间的共同遗传结构。

IF 4.7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Obesity Pub Date : 2025-07-27 DOI:10.1002/oby.24333

Ya Zhan, Na Zhao, Qi-Gang Zhao, Cheng-Xi Wu, Shan-Juan Yuan, Xiu-Juan Yu, Xiao Zheng, Chao-Jie Liu, Rong Hai, Zheng-Qing Liu, Yu-Fang Pei

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引用次数: 0

摘要

目的：研究重度抑郁症（MDD）与腰臀比（WHR）之间的共同遗传结构，为其合并症的生物学机制提供见解。方法：采用大规模全基因组关联研究汇总统计，进行跨性状遗传相关分析、多效变异发现分析、双向孟德尔随机化分析、药物靶点优先化分析。结果：MDD与WHR之间存在显著的遗传相关性（rg = 0.11, p = 4.18 × 10-5）。交叉性状分析鉴定出26个多效位点，包括一个新变异（rs2855812， MICB内含子）。共定位分析证实了6个多效位点。正向孟德尔随机化分析显示，MDD与WHR升高相关(β = 0.079, 95% CI: 0.014-0.143；P = 0.017)，无反向因果关系。药物优先级确定了能够重新靶向MICB， PSORS1C1和C6orf15的药物。富集分析强调免疫途径。结论：我们的研究结果确立了MDD和WHR之间的多效性，暗示失调的免疫代谢途径是共同的机制。优先的药物靶点代表了合并症管理的可转化机会。

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Investigating shared genetic architecture between major depressive disorder and central obesity

Objective

This study investigated the shared genetic architecture between major depressive disorder (MDD) and waist-hip ratio (WHR) to provide insights into the biological mechanisms underlying their comorbidity.

Methods

Using large-scale genome-wide association study summary statistics, we performed cross-trait genetic correlation and pleiotropic variant discovery analyses and bidirectional Mendelian randomization analysis, as well as drug target prioritization analysis.

Results

We identified significant genetic correlation between MDD and WHR (r _g = 0.11, p = 4.18 × 10⁻⁵). Cross-trait analysis identified 26 pleiotropic loci, including a novel variant (rs2855812, intronic to MICB). Colocalization analysis confirmed six pleiotropic loci. Forward Mendelian randomization analysis demonstrated MDD is associated with increased WHR (β = 0.079, 95% CI: 0.014–0.143; p = 0.017), with no reverse causation. Drug prioritization identified agents able to be repurposed targeting MICB, PSORS1C1, and C6orf15. Enrichment analyses highlighted immune pathways.

Conclusions

Our findings establish pleiotropy between MDD and WHR, implicating dysregulated immunometabolic pathways as shared mechanisms. Prioritized drug targets represent translatable opportunities for comorbidity management.

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来源期刊

Obesity 医学-内分泌学与代谢

CiteScore

11.70

自引率

1.40%

发文量

261

审稿时长

2-4 weeks

期刊介绍： Obesity is the official journal of The Obesity Society and is the premier source of information for increasing knowledge, fostering translational research from basic to population science, and promoting better treatment for people with obesity. Obesity publishes important peer-reviewed research and cutting-edge reviews, commentaries, and public health and medical developments.