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. 2025 Mar 27;317(1):641. doi: 10.1007/s00403-025-04169-z

The effect of rosacea on neurodegenerative and neuropsychiatric diseases: a two-sample Mendelian randomization study

Xiangjun Hu 1, Dandan Shen 2, Hong Cai 1, Zhangren Yan 2,✉
PMCID: PMC11950073  PMID: 40146360

Abstract

This study aimed to explore the potential causal relationships between rosacea and Parkinson’s disease, Alzheimer’s disease, anxiety disorders, and depression with MR analysis. Genetic data for rosacea and the four neurodegenerative and neuropsychiatric disorders were sourced from GWAS databases. After completing stringent quality control procedures, SNPs meeting significance thresholds were selected as IVs. Our primary statistical analysis was conducted by IVW approach. To investigate the robustness of results, heterogeneity tests, sensitivity analyses, and pleiotropy assessments were conducted. Reverse MR analyses were subsequently carried out to further substantiate the causal relationships. The present study discovered a positive correlation between rosacea and an elevated risk of depression (OR = 1.0015, 95% CI = 1.0002–1.0027, P = 0.02). There is no causal evidence to support a connection between rosacea and Parkinson’s disease, Alzheimer’s disease, or anxiety disorders. Reverse MR analyses indicated no causal associations between these four disorders and the risk of rosacea. The findings reveal that individuals with rosacea may have an elevated risk of depression.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00403-025-04169-z.

Keywords: Mendelian randomization analysis, Rosacea, Depression, Neurodegenerative disease, Neuropsychiatric disease

Introduction

Rosacea is a common chronic inflammatory skin condition characterized by facial erythema, telangiectasia, papules, pustules, and skin dryness, commonly accompanied by subjective symptoms such as tension, burning, and tingling. It primarily affects middle-aged individuals with lighter skin [1], with a global prevalence of about 5.46%, which causes a significant public health burden [2]. Although its pathogenesis has not been fully elucidated, rosacea is generally considered to arise from the interplay of both endogenous and exogenous factors, including genetic predisposition, skin barrier dysfunction, immune dysregulation, neurogenic inflammation, microbial colonization, and environmental triggers [3].

Emerging evidence has revealed that rosacea is not merely a dermatosis but potentially a systemic disease [4]. With the concept of the gut–brain–skin axis being widely discussed, growing evidence suggests potential associations between rosacea and various neurodegenerative and neuropsychiatric conditions, including Parkinson’s disease, Alzheimer’s disease [5, 6], anxiety disorders, and depression. At the molecular level, studies have identified 747 overlapping differentially expressed genes between Alzheimer’s disease and rosacea, involving pathways related to inflammation, metabolism, and cellular apoptosis [7]. Furthermore, research has established angiogenesis and vascular dysfunction as key shared pathogenic mechanisms in these conditions, which indicates the central importance of the neuro-vascular-immune network in their pathophysiology [8–10]. From an epidemiological perspective, a notably high proportion of 18.8% among 70 documented Parkinson’s disease patients were found to have concurrent rosacea [11], suggesting a potential association between rosacea and neurodegenerative disorders. In addition to neurodegenerative disorders, psychological disorder complications are frequently observed among rosacea patients [12]. Current evidence has documented varying manifestations of these psychological impacts, with studies reporting that male patients may experience more intense feelings of stigma, exhibiting higher rates of depression [13], while female patients demonstrate higher proportions of generalized anxiety [14]. Depression has emerged as one of the primary contributors to disability worldwide. Therefore, the psychological implications of rosacea, which can affect individuals globally, warrant particular attention in clinical practice, irrespective of patient gender.

However, current research on the associations between rosacea and neurodegenerative and neuropsychiatric disorders is primarily based on observational studies, making it challenging to establish causal relationships. Mendelian randomization (MR) analysis, a genetic variant-based approach for causal inference, offers a robust method to control for confounding factors and provides new insights into causal relationships between diseases. Therefore, this study sought to determine the potential causal associations between rosacea and four conditions—Parkinson’s disease, Alzheimer’s disease, anxiety, and depression—that significantly impact patients' quality of life, using two-sample MR analysis at the genetic level. The findings may provide new perspectives and scientific evidence for clinical prevention and treatment strategies in rosacea management.

Materials and methods

Study design

This study employed a two-sample MR analysis to examine potential causal relationships between rosacea with neurodegenerative and neuropsychiatric diseases. The analysis was conducted in strict accordance with the STROBE-MR guidelines [15] to ensure transparency and reproducibility, with the complete STROBE-MR checklist provided in Supplementary Table 1. Furthermore, to establish the directionality of causal relationships, we implemented a bidirectional MR study design, which separately evaluates the causal effects of rosacea on neurodegenerative and neuropsychiatric disorders (forward MR) and the potential reverse causal effects of these disorders on rosacea (reverse MR).

Data sources

All data in this study were obtained from open Genome-Wide Association Studies (GWAS) databases. The specific datasets and their characteristics were as follows: For the exposure variable, rosacea data were derived from the "finn-b-L12_ROSACEA" dataset, comprising 1195 cases and 211,139 controls, with 16,380,452 SNPs. For outcome variables, Parkinson’s disease data were obtained from the "finn-b-G6_PARKINSON" dataset, including 2162 cases and 216,630 controls, with 16,380,466 SNPs. Alzheimer’s disease data were sourced from the "ieu-b-5067" dataset, containing 954 cases and 487,331 controls, with 12,321,875 SNPs. Anxiety disorder data were extracted from the "finn-b-F5_ALLANXIOUS" dataset, consisting of 12,513 cases and 198,110 controls, with 16,380,449 SNPs. Depression data were acquired from the "ebi-a-GCST90038650" dataset, encompassing 27,568 cases and 457,030 controls, with 9,587,836 SNPs. Detailed characteristics of these datasets are presented in Table 1.

Table 1.

Baseline characteristics: database of rosacea and neurodegenerative and neuropsychiatric disorders

Phenotype Year GWAS ID Population Sex Ncase Ncontrol Number of SNPs
Rosacea 2021 finn-b-L12_ROSACEA European F/M 1,195 2,11,139 1,63,80,452
Parkinson’s disease 2021 finn-b-G6_PARKINSON European F/M 2,162 2,16,630 1,63,80,466
Alzheimer’s disease 2022 ieu-b-5067 European F/M 954 4,87,331 1,23,21,875
Anxiety disorder 2021 finn-b-F5_ALLANXIOUS European F/M 12,513 1,98,110 1,63,80,449
Depression 2021 ebi-a-GCST90038650 European F/M 27,568 4,57,030 95,87,836
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GWAS genome-wide association studies, SNPs single nucleotide polymorphisms, F/M female/male

Selection of instrumental variables

For instrumental variables (IVs) selection, we utilized Single Nucleotide Polymorphisms (SNPs) significantly associated with rosacea as IVs. To ensure the reliability of our findings, all selected IVs were required to strictly satisfy the three core assumptions of two-sample MR analysis: 1). Relevance assumption: The selected instrumental variables must demonstrate strong associations with the exposure variable (rosacea); 2). Independence assumption: The selected IVs must be independent of any potential factors that could misrepresented the causal relationship; 3). Exclusion restriction assumption: The IVs should affect the outcome variables solely through the exposure variable (rosacea), without any direct or indirect alternative pathways. These assumptions are illustrated in Fig. 1.

Fig. 1.

Fig. 1

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The flowchart of the MR analysis. IVs instrumental variables, MR Mendelian randomization

To implement MR analysis, adherence to these three assumptions was essential; therefore, all IVs used for subsequent analysis underwent rigorous screening. To ensure adequate sample size, we set the significance threshold for instrumental variables at P < 5e-06 [16]. To preserve the independence of SNPs, we applied rigorous thresholds with r2 < 0.001 and kb = 10,000. The strength of IVs was evaluated using F-statistics (F = beta2/se2) [17], and SNPs with F-values less than 10 were excluded to ensure significance and minimize the likelihood of weak instrument bias.

Statistical analysis

The primary causal estimates were derived using the Inverse Variance Weighted (IVW) approach. Based on the assumption that all selected SNPs are valid IVs, the IVW method provides precise estimates of causal effects. To examine the heterogeneity of genetic instruments, we implemented Cochrane’s Q test, with P < 0.05 revealing the heterogeneity. To strengthen the reliability of our analysis, we employed multiple sensitivity methods including weighted median (WM), MR-Egger regression, simple mode, and weighted mode methods. Additionally, potential pleiotropy was systematically examined using various analytical tools: MR-PRESSO for global testing and outlier detection, MR-Egger intercept for directional assessment, complemented by funnel and forest plots for visual evaluation, collectively ensuring the validity and robustness of our causal estimates. Furthermore, we assessed the robustness of our results through leave-one-out analysis, where SNPs were individually removed to observe the effect of remaining SNPs, thereby exploring whether the associations might be substantially influenced by any single influential SNP. Through these methodological approaches, we aimed to provide a comprehensive and robust genetic association analysis.

To comprehensively evaluate causal relationships, we conducted reverse MR analyses using the same statistical methods, with Parkinson’s disease, Alzheimer’s disease, anxiety, and depression as exposures and rosacea as the outcome.

All statistical analyses were performed using R Studio software (version 4.4.1). The causal relationships between rosacea and the aforementioned disorders were analyzed using the "Two Sample MR" package (version 0.6.8), with P < 0.05 considered as evidence of potential causal effects.

Ethical statement

This study utilizes publicly available summary statistics and does not require additional ethical approval.

Results

MR analysis

Using rosacea as the exposure, we initially identified 13 independent SNPs as IVs through rigorous screening. Of these, all 13 SNPs were used to analyze the causal relationships between rosacea and Parkinson’s disease, Alzheimer’s disease, and anxiety, while 12 SNPs were employed for the analysis of rosacea and depression. (To ensure the reliability of the analysis, rs146915541 was excluded due to its absence in the depression GWAS dataset, a common occurrence in two-sample MR studies primarily attributed to differences in genotyping platforms or quality control criteria across GWAS studies.) Preliminary results indicated a causal association between rosacea and the development of depression, while no significant associations were found with Parkinson’s disease, Alzheimer’s disease, or anxiety.

IVW estimates revealed an association between genetically predicted rosacea and risk of depression, as shown in Figs. 2, 3 (OR = 1.0015, 95% CI = 1.0002–1.0027, P = 0.02). MR-Egger (OR = 1.0002, 95% CI = 1.0000–1.0024, P = 0.88), weighted median (OR = 1.0008, 95% CI = 0.9991–1.0026, P = 0.35), simple mode (OR = 1.0013, 95% CI = 1.0000–1.0038, P = 0.34), and weighted mode (OR = 1.0008, 95% CI = 0.9989–1.0026, P = 0.43) methods, consistently indicated a positive correlation between genetic variations in rosacea and depression. No significant heterogeneity (Cochran’s Q test: P = 0.28) or pleiotropy (MR-Egger intercept = 0.0005, P = 0.20) was detected. Detailed results of all analyses are presented in supplementary Tables 2, 3.

Fig. 2.

Fig. 2

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Forest plot (A), leave-one-out analysis (B), scatter plot (C) and funnel plot (D) of the causal effects of rosacea on depression

Fig. 3.

Fig. 3

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MR to estimate the causal relationship of rosacea to neurodegenerative and neuropsychiatric disorders. SNPs single nucleotide-polymorphisms, OR odds ratio, CI confidence interval

For other 3 diseases, IVW analyses showed no significant associations between rosacea and Parkinson’s disease (OR = 0.9857, 95% CI = 0.9059–1.0725, P = 0.74), Alzheimer’s disease (OR = 0.9999, 95% CI = 1.0000–1.0001, P = 0.47), or anxiety (OR = 1.0136, 95% CI = 0.9835–1.0445, P = 0.38). These findings were consistently supported by MR-Egger, weighted median, simple mode, and weighted mode methods (all P > 0.05). Additionally, no significant heterogeneity or pleiotropy was observed in any of these analyses (all Cochran's Q test P > 0.25; all MR-Egger intercept P > 0.20). Detailed results of all analyses are presented in supplementary Tables 4, 5.

Reverse MR analysis

Similarly, using Parkinson’s disease, Alzheimer’s disease, anxiety disorders, and depression as exposure factors, we identified 12, 25, 20, and 32 SNPs respectively for subsequent analysis, following the previously described screening methods. All included SNPs demonstrated F-statistics significantly greater than 10. No potential causal relationships were found between these disorders and rosacea.

Reverse MR analysis revealed no causal associations between rosacea and Parkinson’s disease (OR = 0.93, 95% CI = 0.7745–1.1202, P = 0.45), Alzheimer’s disease (OR = 2.29*101, 95% CI = 2.34*10–9 −2.24 *1011, P = 0.79), anxiety (OR = 0.98, 95% CI = 0.7320–1.3144, P = 0.897), or depression (OR = 1.92*10–2, 95% CI = 1.67*10–5−2.19*101, P = 0.27). Sensitivity analyses showed no significant pleiotropy or heterogeneity (all P > 0.05). Detailed results of all analyses are presented in supplementary Table 4.

Discussion

A Two-Sample MR framework was implemented to assess the relationships between rosacea with neurodegenerative and neuropsychiatric disorders. Our findings revealed that genetic liability to rosacea was causally associated with elevated depression risk. However, no causal relationships were identified between rosacea and Parkinson’s disease, Alzheimer’s disease, or anxiety disorders. Similarly, reverse MR analysis found no causal relationship between these neurodegenerative and neuropsychiatric disorders and rosacea. Interestingly, our findings showed varying degrees of consistency with previous research: while confirming the association between rosacea and depression, our results diverged regarding other neurodegenerative and neuropsychiatric conditions. A North Finnish cohort study demonstrated that rosacea patients had increased risks of developing depressive and anxiety symptoms [18]. In line with the aforementioned Finnish cohort findings, Alexander Egeberg’s research confirmed that rosacea could increase the risk of developing depression and anxiety [19]. Furthermore, comprehensive systematic reviews and meta-analyses synthesizing extensive research data have provided additional support for the higher likelihood of depression and anxiety among rosacea patients [20].

However, our study could not confirm associations between rosacea and Parkinson’s disease, Alzheimer’s disease, or anxiety, which notably differs from previous observational studies. Through a comprehensive analysis of observational studies (case–control, cross-sectional, and cohort designs), Roger Haber et al. identified significant correlations between rosacea and multiple systemic conditions: depression, hypertension, cardiovascular diseases, anxiety, dyslipidemia, diabetes, migraine, rheumatoid arthritis, H. pylori infection, ulcerative colitis, and dementia [21].

Moreover, research demonstrated that patients with rosacea have a 7% increased risk of developing dementia, with a 25% increased risk of developing Alzheimer’s disease [6]. Further research by Egeberg et al. found that patients with rosacea exhibited a 1.71-fold elevated risk of Parkinson’s disease relative to controls, with the risk magnitude further increasing to two-fold in those with ocular manifestations. They also identified rosacea as an independent risk factor for Parkinson’s disease. This association might be attributed to the shared pathogenic mechanism of elevated matrix metalloproteinase (MMP) activity [22]. Abnormal expression of MMPs and antimicrobial peptides (AMPs) has been observed in rosacea patients, and these aberrant factors have also been implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease [6]. However, our MR findings differ from these observational studies, potentially due to confounding factors such as lifestyle and comorbidities. While elevated neuroinflammatory markers in rosacea patients may suggest a link to neurodegenerative diseases, these markers likely reflect environmental influences rather than direct genetic effects. Our MR approach aims to minimize these confounders, suggesting that rosacea may not be a direct genetic risk factor for neurodegenerative diseases, although some residual confounding could still be present.

The positive association between rosacea and depression identified in our study may be mediated through several mechanisms:

  1. Immune-inflammatory pathway

Rosacea pathogenesis is closely associated with multiple factors, including genetic predisposition, neuroinflammation, neurovascular dysregulation, immune dysfunction, UV exposure, skin barrier disruption, and Demodex infestation [23]. These factors may trigger rosacea by activating multiple signaling pathways, including NACHT-LRRPYD-containing protein 3 (NALP3) and toll-like receptor 2 (TLR2) [24]. Moreover, studies have identified increased TLR2 expression in the keratinocytes of rosacea patients, suggesting its critical role in cutaneous immune activation and inflammatory responses [25]. Consequently, rosacea may increase the risk of depression through the interactive mechanisms of neural, endocrine, and immune systems [26]. The skin, functioning as the body’s largest organ and principal defensive barrier against external threats [27], upon barrier disruption, elicits a complex innate immune response cascade, leading to the upregulation and release of various inflammatory mediators, including epidermal antimicrobial peptides, MMPs, pro-inflammatory cytokines, chemokines, and T helper cells, thereby orchestrating the pathophysiological processes underlying rosacea development [28]. Importantly, the chronic inflammatory phenotype of rosacea shows substantial pathophysiological intersection with the mechanistic pathways of depression development.

Substantial evidence from both clinical and experimental studies has established that pro-inflammatory cytokines play fundamental roles in the etiology and progression of depression, highlighting the inflammatory basis of this disorder [29]. Particularly, a comprehensive systematic review conducted by Yishu Yin et al. investigating the complex interplay between depression and systemic inflammation, revealing significantly elevated serum concentrations of multiple pro-inflammatory cytokines and mediators in depression patients. These elevated inflammatory markers, including a spectrum of pro-inflammatory cytokines and mediators such as several interleukin family members (IL-1β, -5, -6, -7, -8), granulocyte colony-stimulating factor (G-CSF), interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), further underscore the crucial role of inflammatory dysregulation in depression pathogenesis [30]. Researchers have also found that elevated levels of IL-1β, IL-17, and IL-8 are positively correlated with anxiety and depressive episodes in rosacea patients. The interactions among these inflammatory cytokines further suggest a potential common inflammatory mechanism linking rosacea and neuropsychiatric disorders [31].Significantly, these same inflammatory mediators have also been found to be aberrantly expressed in rosacea patients [32], suggesting a shared inflammatory profile between these two conditions.

Furthermore, a study from 90 s last century demonstrated altered serum concentrations of substance P, a neuroimmune modulator, in rosacea patients [33]. Particularly, alterations in this neuropeptide have been documented in patients with severe depression [34, 35], providing compelling molecular evidence for the shared neuroinflammatory pathways between these seemingly distinct conditions.

  • (2)

    Neuroendocrine mechanism

The hypothalamic–pituitary–adrenal (HPA) axis, representing the principal neuroendocrine system governing stress responses, demonstrates remarkable sensitivity to cutaneous psychological stress while orchestrating systemic stress adaptation mechanisms. Extensive research has established the pivotal role of HPA axis dysfunction in both rosacea progression [36],and its significant association with a spectrum of emotional and cognitive disorders [37],thereby emerging as a critical mediator in depression pathogenesis [38, 39].

The chronic facial inflammation and persistent cutaneous manifestations characteristic of rosacea frequently precipitate profound psychological consequences, including diminished self-esteem and heightened feelings of stigmatization, potentially culminating in anxiety symptoms. This sustained psychological distress may trigger HPA axis hyperactivation, resulting in dysregulation of cortisol secretion patterns. Consequently, chronic elevation of cortisol levels may disrupt normal emotional homeostasis, potentially initiating a cascade of neurobiological changes that contribute to the development of depressive symptoms.

Moreover, brain-derived neurotrophic factor (BDNF), a critical regulator of neuronal growth, survival, and plasticity, has been implicated in various neuropsychiatric disorders, including depression. Recent findings by Wang et al. indicate that serum BDNF levels are significantly reduced in rosacea patients compared to healthy controls, with even lower levels observed in rosacea patients presenting with comorbid depression [40]. This further reinforces the neurobiological link between rosacea and depression.

  • (3)

    Gut–brain–skin axis

The gut–brain–skin axis refers to a complex bidirectional communication network through which disruptions in the gastrointestinal microbiota may influence both skin homeostasis and neuropsychiatric health [41, 42]. Given the known inflammatory pathways shared between rosacea and conditions like depression, it is plausible that alterations in gut microbiota composition may exacerbate rosacea symptoms while simultaneously contributing to the pathogenesis of mood disorders. Future research could explore how modulation of the gut microbiome might affect both skin inflammation and psychological health in rosacea patients.

The intricate interplay between the peripheral immune system and central nervous system is mediated through a sophisticated network of neural, endocrine, and immune pathways. Within this complex network, peripheral inflammatory signals can modulate central nervous system function through three distinct but interconnected mechanisms: 1) Direct traversal of inflammatory mediators across the blood–brain barrier (BBB), allowing systemic inflammatory molecules to directly influence neural function; 2) Activation of BBB endothelial cells, triggering the production of secondary inflammatory signals and potentially compromising barrier integrity; and 3) Neural transmission routes, particularly via the vagus nerve, providing rapid communication between peripheral inflammation and central nervous system responses. These converging inflammatory signals subsequently initiate a cascade of neuroinflammatory events within the central nervous system, characterized by microglial activation, perturbations in neurotransmitter metabolism, and disruption of neural plasticity. Particularly, this complex neuroimmune interaction provides a mechanistic framework explaining how peripheral inflammation, such as that observed in chronic inflammatory skin conditions like rosacea, may fundamentally influence central nervous system function and mood regulation. This pathway potentially elucidates one of the key mechanisms by which chronic cutaneous inflammation may contribute to the development or exacerbation of depressive symptoms through sustained neuroinflammatory processes.

Moreover, our study revealed no significant causal relationships between rosacea and Alzheimer’s disease, Parkinson’s disease, or anxiety, findings that may be attributed to several factors:

  1. Methodological differences

The validity of our IVs was rigorously assessed, with all selected SNPs demonstrating F-statistics greater than 10, thereby substantially reducing potential bias from weak instruments. Moreover, our comprehensive sensitivity analyses, encompassing heterogeneity tests, pleiotropy assessments, and leave-one-out analyses, further reinforced the precision of our causal estimates and established the robustness of our findings. However, it is important to note that MR studies inherently rely on several key assumptions, including the assumption that genetic variants affect the outcome only through the exposure of interest, which may not always hold true in complex biological systems.

  • (2)

    Potential confounding factors

Rosacea frequently manifests as part of a complex multi-system disorder, demonstrating significant comorbidity with various systemic conditions, including gastrointestinal disorders [43], immunological dysfunctions [44], and cardiovascular abnormalities [45]. While MR analysis is designed to minimize confounding through the use of genetic instruments, residual confounding remains a significant concern. This residual confounding can arise when genetic variants used as instruments are correlated with unmeasured confounding factors, or when they affect the outcome through pathways independent of the exposure (horizontal pleiotropy). In the context of rosacea, the potential for residual confounding warrants particular attention due to the disease's complex inflammatory mechanisms and their interactions with multiple physiological systems. These concurrent pathological conditions may account for the associations documented in previous observational studies. The correlations reported in previous studies warrant careful interpretation: they may either represent spurious associations stemming from methodological limitations, or more importantly, reflect the influence of yet-unidentified confounding factors in the complex relationship between rosacea and neurodegenerative and neuropsychiatric conditions. This alternative explanation is particularly compelling when considering the intricate nature of systemic inflammation and its cascading effects across multiple physiological systems, suggesting that the observed associations might be mediated through broader inflammatory pathways rather than direct causation by rosacea. Thus, the multifactorial nature of rosacea may be linked to its broad spectrum of systemic comorbidities.

  • (3)

    Study limitations

Despite implementing rigorous statistical methodologies, several important limitations of our study warrant consideration. Primarily, the GWAS data utilized in this analysis were derived exclusively from populations of European ancestry, potentially constraining the generalizability of genetic variation patterns across diverse ethnic groups. This limitation is particularly significant as genetic architecture, environmental factors, and disease manifestations can vary substantially across different populations. The lack of diverse ethnic representation in genetic databases represents a crucial gap in our understanding of these associations in non-European populations. Furthermore, although Mendelian randomization is designed to reduce confounding, residual confounding can still occur if the genetic instruments exhibit pleiotropy or are correlated with unmeasured confounders. Additionally, MR studies may be limited by sample size and statistical power, particularly when investigating complex traits with modest genetic effects. Significantly, while our MR analysis yielded no statistical associations, this finding does not conclusively eliminate the possibility of intrinsic biological connections that may exist beyond the scope of genetic analysis. The complexity of neuropsychiatric disorders and their relationship with inflammatory conditions like rosacea may involve sophisticated biological mechanisms that remain undiscovered, or intricate pathways that current genetic data cannot fully capture. Observational studies, due to their methodological limitations, cannot definitively establish whether rosacea directly causes neuropsychiatric disorders, pointing to a knowledge gap in our current scientific understanding. This limitation emphasizes the pressing need for comprehensive mechanistic investigations, including molecular and cellular studies, to better elucidate the potential biological intersections between dermatological conditions and neuropsychiatric manifestations. Such future research may reveal novel pathways and mechanisms that bridge the gap between our current genetic findings and previously observed clinical associations.

Conclusion

Rosacea and depression are interconnected through chronic inflammation and neuroimmune dysregulation. Elevated levels of pro-inflammatory cytokines and neuropeptides in rosacea perturb neuroendocrine-immune crosstalk, thereby fostering neuroinflammation. Stress-induced dysregulation of the HPA axis further amplifies inflammatory processes, thereby exacerbating depressive symptoms. Our study confirms a causal association between rosacea and increased risk of depression, although no significant relationships were identified with other neuropsychiatric disorders. Clinically, these findings suggest: (1) integrating depression screening into rosacea management, especially for severe cases; (2) exploring anti-inflammatory therapies for dual dermatological and psychiatric benefits; and (3) adopting multidisciplinary care models combining dermatology and mental health expertise. Despite the availability of various therapeutic options for rosacea, managing refractory and severe cases remains a significant challenge for dermatologists [46]. Emerging evidence supports psychological interventions and lifestyle modifications as adjunctive strategies for both conditions. Future research directions should focus on several key areas: first, elucidating the molecular mechanisms underlying the relationship between rosacea and depression; second, conducting prospective studies to validate these causal relationships; and third, exploring targeted therapeutic strategies. Subsequent research endeavors combine multiple methodological approaches, including both genetic and non-genetic studies, to provide a more complete understanding of these complex relationships. Clinical trials evaluating anti-neuroinflammatory agents in comorbid populations are needed. For rosacea patients, it is crucial to establish preventive measures and early intervention protocols for depression management. This includes developing risk prediction models and patient education programs to improve disease coping. These findings provide new perspectives for rosacea treatment, emphasizing the importance of monitoring patients’ psychological well-being in clinical practice while offering novel directions for future research. This integrated approach to rosacea management, considering both dermatological and psychological aspects, may lead to more comprehensive and effective therapeutic strategies.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 47 KB) (46.4KB, docx)
Supplementary file2 (XLS 24 KB) (23.5KB, xls)
Supplementary file3 (XLS 21 KB) (21KB, xls)
Supplementary file4 (XLS 25 KB) (24.5KB, xls)
Supplementary file5 (XLS 21 KB) (20.5KB, xls)
Supplementary file6 (XLS 22 KB) (22KB, xls)
Supplementary file7 (XLS 42 KB) (42KB, xls)

Author contributions

Yan designed this study, with Cai taking charge of data collection and analysis. The initial research manuscript was authored by Hu while Shen was responsible for revising the manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (DOCX 47 KB) (46.4KB, docx)
Supplementary file2 (XLS 24 KB) (23.5KB, xls)
Supplementary file3 (XLS 21 KB) (21KB, xls)
Supplementary file4 (XLS 25 KB) (24.5KB, xls)
Supplementary file5 (XLS 21 KB) (20.5KB, xls)
Supplementary file6 (XLS 22 KB) (22KB, xls)
Supplementary file7 (XLS 42 KB) (42KB, xls)

Data Availability Statement

No datasets were generated or analysed during the current study.

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