Chang Kao-Jung, Wu Hsin-Yu, Chiang Pin-Hsuan, Hsu Yu-Tien, Weng Pei-Yu, Yu Ting-Han, Li Cheng-Yi, Chen Yu-Hsiang, Dai He-Jhen, Tsai Han-Ying, Chang Yu-Jung, Wu You-Ren, Yang Yi-Ping, Li Cheng-Ta, Hsu Chih-Chien, Chen Shih-Jen, Chen Yu-Chun, Cheng Ching-Yu, Hsieh Ai-Ru, Chiou Shih-Hwa
Department of Medical Research, Taipei Veterans General Hospital, 112201 No.201, Sec. 2, Shipai Rd., Beitou District, Taipei, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, 112304 No. 155, Sec. 2, Linong St. Beitou District, Taipei, Taiwan; Department of Ophthalmology, Taipei Veterans General Hospital, 112201 No.201, Sec. 2, Shipai Rd., Beitou District, Taipei, Taiwan; Department of Medical Education, Taipei Veterans General Hospital, 112201 No.201, Sec. 2, Shipai Rd., Beitou District, Taipei, Taiwan.
Department of Medical Research, Taipei Veterans General Hospital, 112201 No.201, Sec. 2, Shipai Rd., Beitou District, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, 112304 No. 155, Sec. 2, Linong St. Beitou District, Taipei, Taiwan.
J Adv Res. 2025 Mar;69:197-213. doi: 10.1016/j.jare.2024.03.015. Epub 2024 Mar 27.
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 (meta-analysis, genome-wide association study [GWAS] and Mendelian randomization [MR]) to elucidate the association, common pathways and causality between DED and DEP.
A meta-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 meta-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 (p 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.
干眼症（DED）和抑郁症（DEP）的临床表现常常同时出现。然而，这种关联的强度和潜在机制尚不确定。
为此，我们开展了一项三段式研究，采用多模态结果（荟萃分析、全基因组关联研究[GWAS]和孟德尔随机化[MR]）来阐明DED与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项病例对照研究的荟萃分析，以确认DED与DEP的关联。接下来，我们在东亚台湾生物银行（TWB）和欧洲英国生物银行（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）以寻找分子相互作用和共同途径。为了进一步阐明DED和DEP中激活的途径，对来自基因表达综合数据库的RNA测序样本进行了系统转录组综述。最后，进行了48项MR实验，以检验DED与DEP之间的双向因果关系。
我们的荟萃分析表明，DED患者的DEP患病率增加（OR = 1.83），而DEP患者患DED的风险同时更高（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）和多效性功能基因导致了两种疾病的表型。通过蛋白质-蛋白质相互作用和本体收敛，我们总结了免疫激活本体下的多效性功能基因，这通过转录组系统综述得到了进一步验证。重要的是，TWB和UKB人群中的逆方差加权（IVW）-MR实验（p值<0.001）支持了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与DEP之间的双向因果关系仍然存在。
综合多模态证据，我们巩固了DED与DEP之间的关联和因果关系。
