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

Guorui Zhao; Zhe Lu; Yundan Liao; Yaoyao Sun; Yuyanan Zhang; Zhewei Kang; Xiaoyang Feng; Junyuan Sun; Weihua Yue

doi:10.1016/j.jare.2024.05.002

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

J Adv Res. 2024 May 11:S2090-1232(24)00179-6. doi: 10.1016/j.jare.2024.05.002. Online ahead of print.

Authors

Guorui Zhao¹, Zhe Lu¹, Yundan Liao¹, Yaoyao Sun¹, Yuyanan Zhang¹, Zhewei Kang¹, Xiaoyang Feng¹, Junyuan Sun¹, Weihua Yue²

Affiliations

¹ Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China.
² Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing 100191, China; PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China; Chinese Institute for Brain Research, Beijing 102206, China. Electronic address: dryue@bjmu.edu.cn.

PMID: 38735387
DOI: 10.1016/j.jare.2024.05.002

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.