A Positive Causal Effect of Shrimp Allergy on Major Depressive Disorder Mediated by Allergy- and Immune-Related Pathways in the East Asian Population

Abstract

Background: Observational studies have implied a potential correlation between allergic diseases and major depressive disorder (MDD). However, the relationship is still inconclusive as it is likely to be interfered with by substantial confounding factors and potential reverse causality. The present study aimed to investigate causal correlation of the two diseases by a Mendelian randomization (MR) study and further elucidate the underlying molecular mechanisms.

Methods: With the biggest summary datasets of a genome-wide association study (GWAS) in the East Asian population, we conducted a two-sample, bidirectional MR study to assess the causal correlation between shrimp allergy (SA) and MDD. Subsequently, we identified the pleiotropic genes' susceptibility to the two diseases at whole-genome and tissue-specific levels, respectively. Enriched GO sets and KEGG pathways were also discovered to elucidate the potential underlying mechanisms.

Results: With the most suitable MR method, SA was identified as a causal risk factor for MDD based on three different groups of independent genetic instruments, respectively (p < 2.81 × 10^-2). In contrast, we did not observe a significant causal effect of MDD on SA. The GWAS-pairwise program successfully identified seven pleiotropic genetic variants (PPA3 > 0.8), indicating that the two diseases indeed have a shared genetic basis. At a whole-genome level, the MAGMA program identified 44 pleiotropic genes, which were enriched in allergy-related pathways, such as antigen processing and presentation pathway (p = 1.46 × 10^-2). In brain-specific tissue, the S-MultiXcan program found 17 pleiotropic genes that were significantly enriched in immune-related pathways and GO sets, including asthma-related pathway, T-cell activation-related, and major histocompatibility complex protein-related GO sets. Regarding whole-blood tissue, the program identified six pleiotropic genes that are significantly enriched in tolerance induction-related GO sets.

Conclusions: The present study for the first time indicated a significant causal effect of SA on the occurrence of MDD, but the reverse was not true. Enrichment analyses of pleiotropic genes at whole-genome and tissue-specific levels implied the involvement of allergy and immune-related pathways in the shared genetic mechanism of the two diseases. Elucidating the causal effect and the acting direction may be beneficial in reducing the incidence rate of MDD for the massive group of SA patients in the East Asian region.

Keywords: East Asian; Mendelian randomization; major depressive disorder; pleiotropic genes; shared genetic basis; shrimp allergy.

Figure 1

Schematic diagram of principal MR analyses and main flowchart of this study. (A,B) Schematic diagram for exploring bidirectional causal effects between SA and MDD; (C,D) Schematic diagram for investigating causal effect of SA on MDD or MDD on SA with independent genetic instrumental variables using pre-set criteria.

Figure 2

Scatter plots showing significant causal effects between SA and MDD. (A–C) Significant causal effects of SA on MDD with IVs with p-value below 5 × 10⁻⁶, 5 × 10⁻³ and F > 10, respectively; (D,E) Causal effects of MDD on SA with IVs with p-value below 5 × 10⁻³ and F > 10, respectively.

Figure 3

Enrichment analyses of gene ontology sets for pleiotropic genes of SA and MDD from the GWAS-PW program. X-axis: The GO terms from left to rights belong to biological process, cellular component and molecular function, respectively; Y-axis: −log₁₀(p-value).

Figure 4

Enrichment analyses of KEGG pathways for pleiotropic genes at a whole-genome level in MAGMA program (A) and in brain tissue by the SMultiXcan program (B).

Figure 5

Enrichment analyses of gene ontology sets for pleiotropic genes in brain tissue by the SMultiXcan program. X-axis: The GO terms from left to right belong to biological process, cellular component, and molecular function, respectively; Y-axis: −log₁₀(p-value).

Figure 6

Enrichment analyses of gene ontology sets for pleiotropic genes in whole blood tissue by the PrediXcan program. X-axis: The GO terms from left to right belong to biological process, cellular component, and molecular function, respectively; Y-axis: −log₁₀(p-value).