Association of intestinal anti-inflammatory drug target genes with psychiatric Disorders: A Mendelian randomization study

Abstract

Introduction: Psychiatric disorders present a substantial global public health burden with limited drug options. The gut-brain axis connects inflammatory bowel diseases and psychiatric disorders, which often have comorbidities. While some evidence hints at anti-inflammatory drugs aiding in treating psychiatric conditions, the specific effects of intestinal anti-inflammatory drugs remain unclear.

Objectives: This study investigates the causal effect of intestinal anti-inflammatory drug targets on psychiatric disorders. We hypothesize that these drug targets may offer new insights into the treatment and prevention of such disorders. Additionally, we explore gut microbiota's mediating role between drug target genes and psychiatric disorders.

Methods: We performed two-sample Mendelian randomization (MR) using summary data from existing expression quantitative trait loci (eQTL) and protein QTL in the brain, along with public genome-wide association studies of disease. We also explored gut microbiota's mediating effect. The statistics encompassed six psychiatric disorders involving 9,725-500,199 individuals. Colocalization analysis enhanced the MR evidence.

Results: We uncovered a causal link between TPMT (a target of olsalazine) expression in the amygdala and bipolar disorder (BD) risk (odds ratio [OR] = 1.08; P = 4.29 × 10^-4). This association was observed even when the sigmoid colon and whole blood eQTL were considered as exposures. Colocalization analysis revealed a shared genetic variant (rs11751561) between TPMT expression and BD, with a posterior probability of 61.6 %. Interestingly, this causal effect was influenced by a decrease in the gut microbiota abundance of the genus Roseburia (effect proportion = 10.05 %). Moreover, elevated ACAT1 expression was associated with higher obsessive-compulsive disorder risk (OR = 1.62; P = 3.64 × 10^-4; posterior probability = 3.1 %).

Conclusion: These findings provide novel targets for the treatment of psychiatric disorders, underscore the potential of repurposing olsalazine, and emphasize the importance of TPMT and ACAT1 in future drug development.

Keywords: Anti-inflammatory; Drug target gene; Gut microbiota; Gut-brain axis; Mendelian Randomization; Psychiatric disorder.

Graphical abstract

Fig. 1

Study design and summary results. β1and β2 denote to the gene–exposure and gene–outcome association, respectively; β represents the causal association between exposure and outcome, where β = β2/β1. BD, bipolar disorder; eQTL, expression quantitative trait loci. GTEx, Genotype-Tissue Expression; GWAS, genome-wide association study; FDR, false-discovery rate; MR, mendelian randomization; IVs, instrumental variables; OCD, obsessive–compulsive disorder; WHOCC, World Health Organization Collaborating Centre.

Fig. 2

Summary suggestively significant results of MR from drug target genes expression and psychiatric disorders. The highlighted red indicates that FDR correction has been passed. ADHD, attention deficit hyperactivity disorder; ASD, autism spectrum disorder; BD, bipolar disorder; CI, confidence interval; MDD, major depressive disorder; MR, Mendelian Randomization; OCD, obsessive–compulsive disorder; SZ, schizophrenia; OR, odds ratio; SNP, single nucleotide polymorphism. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

A) LocusCompare plots comparing eQTL results for TPMT and GWAS for BD. The plots show as lead SNP that with the highest posterior probability according to coloc and other SNPs are colored according to their LD r² with the lead SNP. B) Sensitivity analysis for colocalization of TPMT and BD in the rule of H4 > 0.5. The panels on the left displays local Manhattan plots for the two traits, while the panels on the right illustrate prior and posterior probabilities for H0-H4 as a function of p₁₂. The dashed vertical line represents the value of p₁₂ used in the initial analysis (the value about which sensitivity is to be checked). In the green region, the conclusion of colocalization looks quite robust. SNP, single nucleotide polymorphism. C) LocusCompare plots comparing eQTL results for ACAT1 and GWAS for OCD. D) Sensitivity analysis for colocalization of ACAT1 and OCD in the rule of H4 > 0.5. E and F) TPMT and ACAT1 expression patterns from single-cell RNA-seq data. Cell types abbreviations: L2/3 Upper-layer excitatory neurons, AST-FB Fibrous astrocytes, AST-PP Protoplasmic astrocytes, L5/6-CC Deep-layer cortico-cortical excitatory projection neurons, IN-SV2C SV2C expressing interneurons, IN-VIP VIP interneurons, Oligodendrocytes Oligodendrocytes, IN-SST Somatostatin interneurons, L4 Layer 4 excitatory neurons, Neu-mat Immature neurons, L5/6 Deep-layer cortico-subcortical excitatory projection neurons, IN-PV Parvalbumin interneurons, Endothelial endothelial neurons, Microglia microglia, Neu-NRGN-II NRGN expressing neurons, Neu-NRGN-I NRGN expressing neurons, OPC oligodendrocyte precursor cells. BD, bipolar disorder; chr, chromosome; GWAS, genome-wide association study; eQTL, expression quantitative trait loci; OCD, obsessive–compulsive disorder; SNP, single nucleotide polymorphism. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

A) Circular manhattan plot MR results of TPMT expression and 207 taxa gut microbiota. The red circular dotted line represents the 0.05 threshold. B) The MR effects of 5 taxa gut microbiota and BD risk. BD, bipolar disorder; CI, confidence interval; MR, Mendelian Randomization. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)