The clinical presentations of dry eye disease (DED) and depression (DEP) often comanifest. However, the robustness and the mechanisms underlying this association were undetermined. To this end, we set up a three-segment study that employed multimodality results (-analysis, genome-wide association study [GWAS] and Mendelian randomization [MR]) to elucidate the association, common pathways and causality between DED and DEP. A -analysis comprising 26 case−control studies was first conducted to confirm the DED-DEP association. Next, we performed a linkage disequilibrium (LD)-adjusted GWAS and targeted phenotype association study (PheWAS) in East Asian TW Biobank (TWB) and European UK Biobank (UKB) populations. Single-nucleotide polymorphisms (SNPs) were further screened for molecular interactions and common pathways at the functional gene level. To further elucidate the activated pathways in DED and DEP, a systemic transcriptome review was conducted on RNA sequencing samples from the Gene Expression Omnibus. Finally, 48 MR experiments were implemented to examine the bidirectional causation between DED and DEP. Our -analysis showed that DED patients are associated with an increased DEP prevalence (OR = 1.83), while DEP patients have a concurrent higher risk of DED (OR = 2.34). Notably, cross-disease GWAS analysis revealed that similar genetic architecture (r = 0.19) and pleiotropic functional genes contributed to phenotypes in both diseases. Through protein−protein interaction and ontology convergence, we summarized the pleiotropic functional genes under the ontology of immune activation, which was further validated by a transcriptome systemic review. Importantly, the inverse variance-weighted (IVW)-MR experiments in both TWB and UKB populations ( value <0.001) supported the bidirectional exposure-outcome causation for DED-to-DEP and DEP-to-DED. Despite stringent LD-corrected instrumental variable re-selection, the bidirectional causation between DED and DEP remained. With the multi-modal evidence combined, we consolidated the association and causation between DED and DEP.

中文翻译：

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解码和重建干眼与抑郁症之间的疾病关系：一项包括荟萃分析、遗传途径和孟德尔随机化的多模式研究

干眼病（DED）和抑郁症（DEP）的临床表现常常同时出现。然而，这种关联的稳健性和潜在机制尚未确定。为此，我们建立了一项三段研究，采用多模态结果（分析、全基因组关联研究 [GWAS] 和孟德尔随机化 [MR]）来阐明 DED 和 DEP 之间的关联、共同途径和因果关系。首先进行了一项包含 26 项病例对照研究的分析，以确认 DED-DEP 关联。接下来，我们在东亚 TW 生物库 (TWB) 和欧洲英国生物库 (UKB) 人群中进行了连锁不平衡 (LD) 调整的 GWAS 和靶向表型关联研究 (PheWAS)。在功能基因水平上进一步筛选单核苷酸多态性（SNP）的分子相互作用和共同途径。为了进一步阐明 DED 和 DEP 中的激活途径，对基因表达综合库的 RNA 测序样本进行了系统转录组审查。最后，进行了 48 个 MR 实验来检查 DED 和 DEP 之间的双向因果关系。我们的分析表明，DED 患者与 DEP 患病率增加相关（OR = 1.83），而 DEP 患者同时存在较高的 DED 风险（OR = 2.34）。值得注意的是，跨疾病 GWAS 分析表明，相似的遗传结构 (r = 0.19) 和多效性功能基因促成了两种疾病的表型。通过蛋白质-蛋白质相互作用和本体融合，我们总结了免疫激活本体下的多效性功能基因，并通过转录组系统综述进一步验证。重要的是，TWB 和 UKB 人群中的逆方差加权 (IVW)-MR 实验（值 <0.001）支持 DED 到 DEP 和 DEP 到 DED 的双向暴露结果因果关系。尽管进行了严格的 LD 校正工具变量重新选择，DED 和 DEP 之间的双向因果关系仍然存在。结合多模态证据，我们巩固了 DED 和 DEP 之间的关联和因果关系。