Evidence for a causal association between psoriasis and psychiatric disorders using a bidirectional Mendelian randomization analysis in up to 902,341 individuals

Wang, Yujie; Wang, Xinquan; Gu, Xiaoyu; Pan, Jie; Ouyang, Zhen; Lin, Wenrui; Zhu, Wu; Wang, Mi; Su, Juan

doi:10.1016/j.jad.2023.05.059

Cited by 9 publications

(6 citation statements)

References 31 publications

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“…In accordance with previously published MR studies ( Cao et al, 2023 ; Wang et al, 2023d ), the present study primarily utilized the largest GWAS summary data on PsA, which was freely accessed from the FinnGen Biobank ( Kurki et al, 2023 ). The FinnGen Biobank study is a nationwide collection of genotyped samples from Finnish individuals, comprising both genetic and lifelong health record data from all participants.…”

Section: Methodsmentioning

confidence: 99%

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Investigating causal associations among gut microbiota, metabolites, and psoriatic arthritis: a Mendelian randomization study

Xu,

Wu,

Wang

et al. 2024

Front. Microbiol.

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BackgroundCurrently, there has been observed a significant alteration in the composition of the gut microbiome (GM) and serum metabolites in patients with psoriatic arthritis (PsA) compared to healthy individuals. However, previous observational studies have shown inconsistent results regarding the alteration of gut microbiota/metabolites. In order to shed light on this matter, we utilized Mendelian randomization to determine the causal effect of GM/metabolites on PsA.MethodsWe retrieved summary-level data of GM taxa/metabolites and PsA from publicly available GWAS statistics. Causal relationships between GM/metabolites and PsA were determined using a two-sample MR analysis, with the IVW approach serving as the primary analysis method. To ensure the robustness of our findings, we conducted sensitivity analyses, multivariable MR analysis (MVMR), and additional analysis including replication verification analysis, LDSC regression, and Steiger test analysis. Furthermore, we investigated reverse causality through a reverse MR analysis. Finally, we conducted an analysis of expression quantitative trait loci (eQTLs) involved in the metabolic pathway to explore potential molecular mechanisms of metabolism.ResultsOur findings reveal that eight GM taxa and twenty-three serum metabolites are causally related to PsA (P < 0.05). Notably, a higher relative abundance of Family Rikenellaceae (ORIVW: 0.622, 95% CI: 0.438–0.883, FDR = 0.045) and elevated serum levels of X-11538 (ORIVW: 0.442, 95% CI: 0.250–0.781, FDR = 0.046) maintain significant causal associations with a reduced risk of PsA, even after adjusting for multiple testing correction and conducting MVMR analysis. These findings suggest that Family Rikenellaceae and X-11538 may have protective effects against PsA. Our sensitivity analysis and additional analysis revealed no significant horizontal pleiotropy, reverse causality, or heterogeneity. The functional enrichment analysis revealed that the eQTLs examined were primarily associated with glycerolipid metabolism and the expression of key metabolic factors influenced by bacterial infections (Vibrio cholerae and Helicobacter pylori) as well as the mTOR signaling pathway.ConclusionIn conclusion, our study demonstrates that Family Rikenellaceae and X-11538 exhibit a strong and negative causal relationship with PsA. These particular GM taxa and metabolites have the potential to serve as innovative biomarkers, offering valuable insights into the treatment and prevention of PsA. Moreover, bacterial infections and mTOR-mediated activation of metabolic factors may play an important role in this process.

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Section: Methodsmentioning

confidence: 99%

Section: Outcome Data Of Psamentioning

confidence: 99%

Investigating causal associations among gut microbiota, metabolites, and psoriatic arthritis: a Mendelian randomization study

Xu,

Wu,

Wang

et al. 2024

Front. Microbiol.

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“…We used a clumping algorithm with a cutoff of r2 = 0.01 and kb = 10000 to select SNPs that were in linkage disequilibrium with each other (28,29). Previous studies have described the methods used for other Mendelian randomization (MR) analyses (30)(31)(32). To assess heterogeneity among instrumental variables (IVs), we employed Cochran's Q test, with a P-value greater than 0.05 indicating no significant heterogeneity.…”

Section: Statistical Analysis For Mendelian Randomizationmentioning

confidence: 99%

“…MR utilizes single nucleotide polymorphisms (SNPs) to simulate randomized controlled trials, aiming to ascertain and explore the causal association between exposure and outcome variables in epidemiological research. By effectively eliminating the confounding effects of extraneous factors and employing genetic variations as instrumental variables (IVs), MR enables the analysis of disease relationships (28)(29)(30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis

Cui,

Tang,

Gao

et al. 2023

Front. Immunol.

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BackgroundThe role of complement component 1q (C1Q) related genes on human atherosclerotic plaques (HAP) is less known. Our aim is to establish C1Q associated hub genes using single-cell RNA sequencing (scRNA-seq) and bulk RNA analysis to diagnose and predict HAP patients more effectively and investigate the association between C1Q and HAP (ischemic stroke) using bidirectional Mendelian randomization (MR) analysis.MethodsHAP scRNA-seq and bulk-RNA data were download from the Gene Expression Omnibus (GEO) database. The C1Q-related hub genes was screened using the GBM, LASSO and XGBoost algorithms. We built machine learning models to diagnose and distinguish between types of atherosclerosis using generalized linear models and receiver operating characteristics (ROC) analyses. Further, we scored the HALLMARK_COMPLEMENT signaling pathway using ssGSEA and confirmed hub gene expression through qRT-PCR in RAW264.7 macrophages and apoE-/- mice. Furthermore, the risk association between C1Q and HAP was assessed through bidirectional MR analysis, with C1Q as exposure and ischemic stroke (IS, large artery atherosclerosis) as outcomes. Inverse variance weighting (IVW) was used as the main method.ResultsWe utilized scRNA-seq dataset (GSE159677) to identify 24 cell clusters and 12 cell types, and revealed seven C1Q associated DEGs in both the scRNA-seq and GEO datasets. We then used GBM, LASSO and XGBoost to select C1QA and C1QC from the seven DEGs. Our findings indicated that both training and validation cohorts had satisfactory diagnostic accuracy for identifying patients with HPAs. Additionally, we confirmed SPI1 as a potential TF responsible for regulating the two hub genes in HAP. Our analysis further revealed that the HALLMARK_COMPLEMENT signaling pathway was correlated and activated with C1QA and C1QC. We confirmed high expression levels of C1QA, C1QC and SPI1 in ox-LDL-treated RAW264.7 macrophages and apoE-/- mice using qPCR. The results of MR indicated that there was a positive association between the genetic risk of C1Q and IS, as evidenced by an odds ratio (OR) of 1.118 (95%CI: 1.013–1.234, P = 0.027).ConclusionThe authors have effectively developed and validated a novel diagnostic signature comprising two genes for HAP, while MR analysis has provided evidence supporting a favorable association of C1Q on IS.

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“…6 A recent Mendelian randomization study concluded that psoriasis is causally related to major depressive disorder and bipolar disorder, even after excluding external confounders such as smoking and alcohol abuse. 7 Neuropeptides, including calcitonin gene-related peptide (CGRP) and substance P (SP), are found to be elevated in both plasma and at lesions among patients with psoriasis. 8 These neuropeptides induce hyperinnervation of skin lesions and promote proliferation of keratin-forming cells and blood vessels.…”

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confidence: 99%

Effects on peripheral and central nervous system of key inflammatory intercellular signalling peptides and proteins in psoriasis

Tang,

Zhao,

Shi

et al. 2024

Experimental Dermatology

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Psoriasis is a chronic systemic inflammatory cutaneous disease. Where the immune system plays an important role in its pathogenesis, with key inflammatory intercellular signalling peptides and proteins including IL‐17 and IL‐23. The psychoneurological system also figures prominently in development of psoriasis. There is a high prevalence of comorbidity between psoriasis and mental health disorders such as depression, anxiety and mania. Patients with psoriasis often suffer from pathological pain in the lesions, and their neurological accidents could improve the lesions in innervated areas. The immune system and the psychoneurological system interact closely in the pathogenesis of psoriasis. Patients with psoriasis exhibit abnormal levels of neuropeptides both in circulating and localized lesion, acting as immunomodulators involved in the inflammatory response. Moreover, receptors for inflammatory factors are expressed in both peripheral and central nervous systems (CNSs), suggesting that nervous system can receive and be influenced by signals from immune system. Key inflammatory intercellular signalling peptides and proteins in psoriasis, such as IL‐17 and IL‐23, can be involved in sensory signalling and may affect synaptic plasticity and the blood–brain barrier of CNS through the circulation. This review provides an overview of the multiple effects on the peripheral and CNS under conditions of systemic inflammation in psoriasis, providing a framework and inspiration for in‐depth studies of neuroimmunomodulation in psoriasis.

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Evidence for a causal association between psoriasis and psychiatric disorders using a bidirectional Mendelian randomization analysis in up to 902,341 individuals

Cited by 9 publications

References 31 publications

Investigating causal associations among gut microbiota, metabolites, and psoriatic arthritis: a Mendelian randomization study

Investigating causal associations among gut microbiota, metabolites, and psoriatic arthritis: a Mendelian randomization study

An integrative analysis of single-cell and bulk transcriptome and bidirectional mendelian randomization analysis identified C1Q as a novel stimulated risk gene for Atherosclerosis

Effects on peripheral and central nervous system of key inflammatory intercellular signalling peptides and proteins in psoriasis

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