Decoding and reconstructing disease relations between dry eye and depression: a multimodal investigation comprising meta-analysis, genetic pathways and Mendelian randomization

Abstract

Introduction: The clinical presentations of dry eye disease (DED) and depression (DEP) often comanifest. However, the robustness and the mechanisms underlying this association were undetermined.

Objectives: 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.

Methods: 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.

Results: 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_G = 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.

Conclusion: With the multi-modal evidence combined, we consolidated the association and causation between DED and DEP.

Keywords: Depression; Dry eye disease; Genome-wide association study; Mendelian randomization; Meta-analysis; Multimodality Biobank.

Graphical abstract

Fig. 1

Study Design Overview. To evaluate the underlying relationship between dry eye disease (DED) and depression (DEP), we performed a three-segment study. First, we reviewed the disease association by literature meta-analysis. Second, we confirmed a two-disease genetic correlation by a genome-wide association study (GWAS) in Taiwan Biobank (TWB) and UK Biobank (UKB), clarifying pathway correlation by gene ontology (GO) and protein−protein interaction (PPI) analysis. Finally, we identified bidirectional causation by regarding single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) in Mendelian randomization (MR).

Fig. 2

Forest plots illustrating associations between dry eye disease (DED) and depression (DEP) in terms of prevalence odds ratio (OR). (A) Association between the prevalence of depression in DED patients versus the control group. (B) Association between the prevalence of DED in depression patients versus the control group. CI, confidence interval; M−H, Mantel–Haenszel.

Fig. 3

Meta-analysis results for the association between dry eye disease (DED) and depression (DEP). (A) Association between the prevalence of depression in DED patients versus the control group. (B) Association between the prevalence of DED in depression patients versus the control group. (C) Association between depression severity in DED patients versus the control group. Since the depression scales varied from study to study, the severity of depression was standardized into a Z score. (D) Association between the Schirmer test (ST) of DED severity in depression patients versus the control group. (E) Association between tear break-up time (TBUT) and DED severity in depression patients versus the control group. NS, not significant (p value >0.05); *, statistically significant with p value <0.05; **, statistically significant with p value <0.01; ****, statistically significant with p value <0.0001.

Fig. 4

Investigation of dry eye disease (DED) and depression (DEP) association through genetic approaches. (A) Chord diagram showing crosswalks between the phoneme and functional single-nucleotide polymorphisms (SNPs) of DED and DEP. (B) Heatmap of the genetic correlation scores between listed ocular and depressive diseases in Taiwan Biobank (TWB). (C) The protein−protein interaction (PPI) network of the functional SNP_DED and SNP_DEP genes derived from TWB and UK Biobank (UKB). (D) The converging ontology flow chart analyzing the functional SNP_DED and SNP_DEP genes.

Fig. 5

Heatmap of the activated common pathways in published dry eye disease (DED) and depression (DEP) transcriptome databases. R-HAS, Reactome Homo sapiens; GSE, Gene Expression Omnibus Series; DC, dendritic cell; SjS, Sjögren's syndrome; PBMC, peripheral blood mononuclear cells; IL, interleukin; and TLR, Toll-like receptors.

Fig. 6

Validation of dry eye disease (DED)-depression (DEP) bidirectional causation using different two-sample Mendelian randomization (TSMR) methods in replicative practices. Scatter plots of (A) TSMR experiments using genome-wide association study (GWAS)-selected SNPs as instrumental variables. Experiments were repeated in both the Taiwan Biobank (TWB) and UK Biobank (UKB). (B) TSMR instrument variables were replaced by conditional and joint association analysis (COJO) and scalable and accurate implementation of generalized mixed model (SAIGE)-corrected GWAS single-nucleotide polymorphisms (SNPs) in UKB. (C) The SNP number needed for TSMR significance and its corresponding effects on the TSMR odds ratio was investigated.