Wenqiang Zhang, Lingli Qiu, Yunjie Liu, Yutong Wang, Mingshuang Tang, Lin Chen, Ben Zhang, Xia Jiang
{"title":"通过综合遗传分析鉴定TMEM106B作为抑郁症和中风的共同潜在药物靶点","authors":"Wenqiang Zhang, Lingli Qiu, Yunjie Liu, Yutong Wang, Mingshuang Tang, Lin Chen, Ben Zhang, Xia Jiang","doi":"10.1155/da/5250758","DOIUrl":null,"url":null,"abstract":"<p><b>Background:</b> The coexistence of depression and stroke has long been observed; however, their intrinsic link has not been fully understood. We aimed to inform the importance of depression intervention as a primary prevention of stroke by investigating shared genetic etiology and causal relationship underlying depression and stroke.</p><p><b>Methods:</b> Leveraging summary statistics from the hitherto largest genome-wide association studies (GWAS) in European-ancestry individuals for depression (<i>N</i><sub>case</sub>/<i>N</i><sub>control</sub> = 294,322/741,438) and stroke (<i>N</i><sub>case</sub>/<i>N</i><sub>control</sub> = 73,652/1,234,808), we performed cross-trait linkage-disequilibrium (LD) score regression and SUPERGNOVA to quantify global and local genetic correlations, cross-trait meta-analysis to identify shared genetic loci, transcriptome-wide association study (TWAS) to detect shared tissue-specific gene expression, and Mendelian randomization (MR) analysis to make causal inference between the two conditions.</p><p><b>Results:</b> We observed a significant positive global genetic correlation between depression and stroke (rg = 0.18, <i>p</i> = 2.92 ×10<sup>−9</sup>). Partitioning the whole genome, we observed one genomic region (11q23.2) presenting a significant local genetic correlation. Cross-trait meta-analysis and TWAS identified two shared genetic loci (<i>TMEM106B</i> and <i>FES</i>) revealing potential shared biological mechanisms involving lysosome localization. MR identified a putative causal association of genetically predicted depression on stroke (odds ratio [OR] = 1.13, 95% confidence interval [CI] = 1.07−1.19, <i>p</i> = 1.12 ×10<sup>−5</sup>). A considerable proportion of this association was mediated through smoking initiation (proportion-mediated [PM] = 44.0%, 95% CI = 19.9%–68.1%, <i>p</i> = 3.42 ×10<sup>−4</sup>), hypertension (PM = 34.0%, 95% CI = 14.5%–53.5%, <i>p</i> = 6.46 ×10<sup>−4</sup>), type 2 diabetes (PM = 19.0%, 95% CI = 8.5%–29.5%, <i>p</i> = 3.78 ×10<sup>−4</sup>), and atrial fibrillation (PM = 10.9%, 95% CI = 0.7%–21.1%, <i>p</i> = 3.61 ×10<sup>−2</sup>), respectively. MR in the reverse direction identified a putative association of genetically predicted stroke on depression (OR = 1.05, 95% CI = 1.01−1.09, <i>p</i> = 1.73 ×10<sup>−2</sup>), which attenuated to nonsignificant when correcting for both correlated and uncorrelated pleiotropy (OR = 1.00, 95% CI = 0.98−1.03, <i>p</i> = 0.88). Drug target MR identified causal associations of genetically predicted <i>TMEM106B</i> level on depression (OR = 0.92, 95% CI = 0.90−0.94, <i>p</i> = 2.04 ×10<sup>−12</sup>) and stroke (OR = 0.90, 95% CI = 0.86−0.95, <i>p</i> = 3.53 ×10<sup>−5</sup>).</p><p><b>Conclusion:</b> Our work highlights a shared genetic basis and a putative causal relationship between depression and stroke, providing novel insights into the primary prevention of stroke by depression intervention.</p>","PeriodicalId":55179,"journal":{"name":"Depression and Anxiety","volume":"2025 1","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2025-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/da/5250758","citationCount":"0","resultStr":"{\"title\":\"Identification of TMEM106B as a Shared Potential Drug Target for Depression and Stroke Through Comprehensive Genetic Analyses\",\"authors\":\"Wenqiang Zhang, Lingli Qiu, Yunjie Liu, Yutong Wang, Mingshuang Tang, Lin Chen, Ben Zhang, Xia Jiang\",\"doi\":\"10.1155/da/5250758\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><b>Background:</b> The coexistence of depression and stroke has long been observed; however, their intrinsic link has not been fully understood. We aimed to inform the importance of depression intervention as a primary prevention of stroke by investigating shared genetic etiology and causal relationship underlying depression and stroke.</p><p><b>Methods:</b> Leveraging summary statistics from the hitherto largest genome-wide association studies (GWAS) in European-ancestry individuals for depression (<i>N</i><sub>case</sub>/<i>N</i><sub>control</sub> = 294,322/741,438) and stroke (<i>N</i><sub>case</sub>/<i>N</i><sub>control</sub> = 73,652/1,234,808), we performed cross-trait linkage-disequilibrium (LD) score regression and SUPERGNOVA to quantify global and local genetic correlations, cross-trait meta-analysis to identify shared genetic loci, transcriptome-wide association study (TWAS) to detect shared tissue-specific gene expression, and Mendelian randomization (MR) analysis to make causal inference between the two conditions.</p><p><b>Results:</b> We observed a significant positive global genetic correlation between depression and stroke (rg = 0.18, <i>p</i> = 2.92 ×10<sup>−9</sup>). Partitioning the whole genome, we observed one genomic region (11q23.2) presenting a significant local genetic correlation. Cross-trait meta-analysis and TWAS identified two shared genetic loci (<i>TMEM106B</i> and <i>FES</i>) revealing potential shared biological mechanisms involving lysosome localization. MR identified a putative causal association of genetically predicted depression on stroke (odds ratio [OR] = 1.13, 95% confidence interval [CI] = 1.07−1.19, <i>p</i> = 1.12 ×10<sup>−5</sup>). A considerable proportion of this association was mediated through smoking initiation (proportion-mediated [PM] = 44.0%, 95% CI = 19.9%–68.1%, <i>p</i> = 3.42 ×10<sup>−4</sup>), hypertension (PM = 34.0%, 95% CI = 14.5%–53.5%, <i>p</i> = 6.46 ×10<sup>−4</sup>), type 2 diabetes (PM = 19.0%, 95% CI = 8.5%–29.5%, <i>p</i> = 3.78 ×10<sup>−4</sup>), and atrial fibrillation (PM = 10.9%, 95% CI = 0.7%–21.1%, <i>p</i> = 3.61 ×10<sup>−2</sup>), respectively. MR in the reverse direction identified a putative association of genetically predicted stroke on depression (OR = 1.05, 95% CI = 1.01−1.09, <i>p</i> = 1.73 ×10<sup>−2</sup>), which attenuated to nonsignificant when correcting for both correlated and uncorrelated pleiotropy (OR = 1.00, 95% CI = 0.98−1.03, <i>p</i> = 0.88). Drug target MR identified causal associations of genetically predicted <i>TMEM106B</i> level on depression (OR = 0.92, 95% CI = 0.90−0.94, <i>p</i> = 2.04 ×10<sup>−12</sup>) and stroke (OR = 0.90, 95% CI = 0.86−0.95, <i>p</i> = 3.53 ×10<sup>−5</sup>).</p><p><b>Conclusion:</b> Our work highlights a shared genetic basis and a putative causal relationship between depression and stroke, providing novel insights into the primary prevention of stroke by depression intervention.</p>\",\"PeriodicalId\":55179,\"journal\":{\"name\":\"Depression and Anxiety\",\"volume\":\"2025 1\",\"pages\":\"\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-09-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1155/da/5250758\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Depression and Anxiety\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1155/da/5250758\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PSYCHIATRY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Depression and Anxiety","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1155/da/5250758","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PSYCHIATRY","Score":null,"Total":0}
引用次数: 0
摘要
背景：抑郁症与脑卒中共存的现象早已被观察到；然而，它们之间的内在联系还没有被完全理解。我们的目的是通过调查抑郁症和中风的共同遗传病因和因果关系，告知抑郁症干预作为中风一级预防的重要性。方法:利用迄今为止最大的欧洲血统抑郁症（Ncase/Ncontrol = 294,322/741,438）和中风（Ncase/Ncontrol = 73,652/1,234,808）全基因组关联研究（GWAS）的汇总统计数据，我们进行了跨性状连锁不平衡（LD）评分回归和SUPERGNOVA，以量化全球和局部遗传相关性，跨性状荟萃分析以确定共享遗传位点。转录组全关联研究（TWAS）检测共享的组织特异性基因表达，以及孟德尔随机化（MR）分析在两种情况之间进行因果推理。结果：我们发现抑郁与脑卒中之间存在显著的全球正遗传相关（rg = 0.18, p = 2.92 ×10−9）。对整个基因组进行划分，我们观察到一个基因组区域（11q23.2）呈现出显著的局部遗传相关性。跨性状荟萃分析和TWAS鉴定出两个共享的遗传位点（TMEM106B和FES），揭示了涉及溶酶体定位的潜在共享生物学机制。MR鉴定出脑卒中与基因预测抑郁之间的推定因果关系（优势比[OR] = 1.13, 95%可信区间[CI] = 1.07 - 1.19, p = 1.12 ×10 - 5）。这种关联的很大一部分是通过吸烟介导的（比例介导[PM] = 44.0%, 95% CI = 19.9%-68.1%, p = 3.42 ×10−4）、高血压（PM = 34.0%, 95% CI = 14.5%-53.5%, p = 6.46 ×10−4）、2型糖尿病（PM = 19.0%, 95% CI = 8.5%-29.5%, p = 3.78 ×10−4）和房颤（PM = 10.9%, 95% CI = 0.7%-21.1%, p = 3.61 ×10−2）。相反方向的MR鉴定出基因预测的中风与抑郁症的推定关联（OR = 1.05, 95% CI = 1.01 - 1.09, p = 1.73 ×10 - 2），当校正相关和不相关的多效性时，这种关联减弱为不显著（OR = 1.00, 95% CI = 0.98 - 1.03, p = 0.88）。药物靶MR鉴定出基因预测的TMEM106B水平与抑郁症（OR = 0.92, 95% CI = 0.90−0.94,p = 2.04 ×10−12）和中风（OR = 0.90, 95% CI = 0.86−0.95,p = 3.53 ×10−5）之间的因果关系。结论：我们的工作强调了抑郁症和中风之间共同的遗传基础和假定的因果关系，为抑郁症干预中风的一级预防提供了新的见解。
Identification of TMEM106B as a Shared Potential Drug Target for Depression and Stroke Through Comprehensive Genetic Analyses
Background: The coexistence of depression and stroke has long been observed; however, their intrinsic link has not been fully understood. We aimed to inform the importance of depression intervention as a primary prevention of stroke by investigating shared genetic etiology and causal relationship underlying depression and stroke.
Methods: Leveraging summary statistics from the hitherto largest genome-wide association studies (GWAS) in European-ancestry individuals for depression (Ncase/Ncontrol = 294,322/741,438) and stroke (Ncase/Ncontrol = 73,652/1,234,808), we performed cross-trait linkage-disequilibrium (LD) score regression and SUPERGNOVA to quantify global and local genetic correlations, cross-trait meta-analysis to identify shared genetic loci, transcriptome-wide association study (TWAS) to detect shared tissue-specific gene expression, and Mendelian randomization (MR) analysis to make causal inference between the two conditions.
Results: We observed a significant positive global genetic correlation between depression and stroke (rg = 0.18, p = 2.92 ×10−9). Partitioning the whole genome, we observed one genomic region (11q23.2) presenting a significant local genetic correlation. Cross-trait meta-analysis and TWAS identified two shared genetic loci (TMEM106B and FES) revealing potential shared biological mechanisms involving lysosome localization. MR identified a putative causal association of genetically predicted depression on stroke (odds ratio [OR] = 1.13, 95% confidence interval [CI] = 1.07−1.19, p = 1.12 ×10−5). A considerable proportion of this association was mediated through smoking initiation (proportion-mediated [PM] = 44.0%, 95% CI = 19.9%–68.1%, p = 3.42 ×10−4), hypertension (PM = 34.0%, 95% CI = 14.5%–53.5%, p = 6.46 ×10−4), type 2 diabetes (PM = 19.0%, 95% CI = 8.5%–29.5%, p = 3.78 ×10−4), and atrial fibrillation (PM = 10.9%, 95% CI = 0.7%–21.1%, p = 3.61 ×10−2), respectively. MR in the reverse direction identified a putative association of genetically predicted stroke on depression (OR = 1.05, 95% CI = 1.01−1.09, p = 1.73 ×10−2), which attenuated to nonsignificant when correcting for both correlated and uncorrelated pleiotropy (OR = 1.00, 95% CI = 0.98−1.03, p = 0.88). Drug target MR identified causal associations of genetically predicted TMEM106B level on depression (OR = 0.92, 95% CI = 0.90−0.94, p = 2.04 ×10−12) and stroke (OR = 0.90, 95% CI = 0.86−0.95, p = 3.53 ×10−5).
Conclusion: Our work highlights a shared genetic basis and a putative causal relationship between depression and stroke, providing novel insights into the primary prevention of stroke by depression intervention.
期刊介绍：
Depression and Anxiety is a scientific journal that focuses on the study of mood and anxiety disorders, as well as related phenomena in humans. The journal is dedicated to publishing high-quality research and review articles that contribute to the understanding and treatment of these conditions. The journal places a particular emphasis on articles that contribute to the clinical evaluation and care of individuals affected by mood and anxiety disorders. It prioritizes the publication of treatment-related research and review papers, as well as those that present novel findings that can directly impact clinical practice. The journal's goal is to advance the field by disseminating knowledge that can lead to better diagnosis, treatment, and management of these disorders, ultimately improving the quality of life for those who suffer from them.
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