Category: 8. Health

Background

Obstructive sleep apnea (OSA) is a common sleep disorder, with a prevalence of approximately 23% in women and nearly 50% in men.¹ The development of OSA is influenced by both anatomical and non-anatomical risk factors. Anatomical factors, such as obesity and craniofacial abnormalities, promote upper airway collapse and obstruction during sleep.² Non-anatomical factors include heightened airway collapsibility, a low respiratory arousal threshold, and unstable ventilatory control.³ The hallmark feature of OSA is intermittent hypoxia during sleep, which significantly increases the risk of cardiovascular, neurological, and metabolic disorders.⁴

The potential role of the gut microbiota in human disease development has received increasing attention over the past decade. In particular, microbiota dysbiosis has been implicated in the pathogenesis of OSA.⁵ Disruption of the gut microbiota has been associated with altered sleep-wake architecture⁶ and reduced sleep efficiency.^7,8 It may also impair the ventilatory response to hypercapnia,⁹ thereby contributing to unstable ventilatory control in patients with OSA. In addition, microbiota dysbiosis contributes to the development of obesity,¹⁰ a key risk factor for OSA. Probiotics have emerged as promising adjunctive interventions for OSA, primarily through their ability to reduce systemic inflammation and enhance gut barrier integrity.¹¹ Faecal microbiota transplantation has also been shown to partially alleviate cardiovascular disturbances induced by chronic intermittent hypoxia.¹² Moreover, the probiotic strain Lactobacillus rhamnosus GG has demonstrated beneficial effects in experimental models of OSA, including improvements in metabolic disturbances,¹³ mitigation of hypertension severity,¹⁴ attenuation of cardiac remodeling and inflammation.¹⁵ Accordingly, elucidating the role of gut microbiota in the pathogenesis of OSA holds substantial promise, and the identification of effective probiotic-based interventions may offer a novel therapeutic avenue.

Metabolites and their related biochemical pathways have emerged as important contributors to the development of OSA.¹⁶ An increased prevalence of OSA has been reported in patients with neurodegenerative disorders, potentially related to impairments in central respiratory control and functional alterations of the upper airway.¹⁷ The nervous system and gastrointestinal tract communicate through a bidirectional network of signaling pathways, collectively referred to as the microbiota–gut–brain axis, which involves the vagus nerve, immune mechanisms, and microbiota-associated metabolic and molecular products. Emerging evidence suggests that this axis plays a pivotal role in the pathogenesis of neurodegenerative diseases.¹⁸ These findings highlight the potential importance of microbiota–gut–brain axis related pathways in the pathogenesis and progression of OSA, suggesting that further research in this area is warranted. Previous studies have reported the involvement of metabolites and microbiota-related metabolites in the development and progression of OSA. Xu et al reported correlations between alterations in the oral microbiome and disruptions in urinary metabolites in children with OSA.¹⁹ Using Mendelian randomization (MR), Yan et al identified several gut microbiota and microbiota-related metabolites as potential independent risk factors for OSA.²⁰ Therefore, investigating the relationship between the gut microbiota and OSA, and further exploring the potential mediating role of metabolites, is of substantial significance.

MR provides a powerful framework for investigating the causal relationship between gut microbiota and OSA.²¹ In MR analysis, genetic variants are used as instrumental variables (IVs) for exposure traits, enabling the estimation of causal effects on clinical outcomes while minimizing confounding and reverse causation. In this study, we performed two-sample and two-step MR analyses using summary-level data from the genome-wide association studies (GWAS) on gut microbiota, plasma metabolites, and OSA. This study primarily focused on identifying gut microbiota and potential mediator metabolites that may confer protective effects against OSA, with the aim of uncovering novel therapeutic targets and providing preliminary insights into the underlying mechanisms.

Methods

Study Design

This study was conducted using a two-sample MR framework, with single nucleotide polymorphisms (SNPs) selected as IVs. MR relies on three key assumptions: i the IVs are strongly associated with the exposure; ii the IVs are not associated with any confounders; and iii the IVs affect the outcome solely through the exposure, without exerting a direct effect on the outcome.

An overview of the study design is provided in Figure 1. First, a two-sample MR analysis was performed to explore the potential causal relationship between gut microbiota and OSA. To reduce potential functional heterogeneity, microbial taxa within the same genus or family that showed divergent associations with the OSA were excluded. Only microbial taxa associated with a reduced risk of OSA were retained for further analysis. Second, potential mediators were identified according to the following steps. Step 1: An exploratory two-sample MR analysis was conducted to identify metabolites potentially involved in the development and progression of OSA. To account for multiple testing, the false discovery rate (FDR) was controlled using the Benjamini–Hochberg procedure. Metabolites were prioritized based on inverse variance weighted (IVW) P values adjusted for FDR (P_FDR). The biological relevance of these metabolites was further assessed using the Human Metabolome Database (HMDB) (Version 5.0). Ultimately, the top 10 metabolites with potential biological significance were selected as candidate mediators for subsequent analyses (Supplementary Table 1). Step 2: Potential mediators of the association between gut microbiota and OSA were identified based on the following criteria: i a two-sample MR analysis was conducted to assess the causal relationship between each selected protective taxon and candidate mediator. P values were adjusted for multiple comparisons using the FDR correction. The directionality of the associations was confirmed to be unidirectional. ii a two-sample MR analysis was performed to evaluate the causal effect of each candidate mediator on the OSA, using a more stringent SNP selection threshold (P < 5e-6) and excluding SNPs associated with known confounders. iii the direction of the association between the mediator and OSA had to be opposite to that between the selected protective taxa and the mediator. Third, the mediating effects of the identified metabolites on the causal pathway linking gut microbiota to OSA were quantified using a two-step MR approach. In the initial step, we employed a two-sample MR analysis to assess the total direct effect of gut microbiota on OSA risk (β0). In the subsequent step, we estimated the effect of gut microbiota on plasma metabolites (β1) and the effect of plasma metabolites on OSA (β2), allowing us to calculate the indirect effect (β1 × β2). The proportion of the mediated effect was determined by dividing β1 × β2 by the total effect (β0).

Figure 1 Overview of the study design. (A) Protective gut microbiota associated with reduced OSA risk were identified using two-sample MR analysis. (B) The top 10 candidate metabolites were selected based on FDR-adjusted IVW results and biological relevance derived from the HMDB. (C) Potential mediators were identified through a three-step process involving causal links between gut microbiota and metabolites, metabolites-OSA associations, and consistent directional effects. (D) A two-step MR analysis was conducted to quantify the mediation effect linking gut microbiota to OSA through the selected metabolites. MR analyses were primarily conducted using the IVW method, with complementary approaches including MR-Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses included Cochran’s Q statistic, MR-Egger intercept test, MR-Pleiotropy Residual Sum and Outlier method, MR Steiger directionality test, and leave-one-out approach. Abbreviations: OSA, obstructive sleep apnea; GWAS, genome-wide association study; SNPs, single nucleotide polymorphisms; MR, mendelian randomization; IVW, inverse variance weighted; FDR, false discovery rate; PFDR, P values adjusted for FDR; HMDB, Human Metabolome Database.

Data Sources

We garnered the GWAS data for the gut microbiota from the Dutch Microbiome Project.²² The Dutch Microbiome Project analyzed feces from 7,738 individuals of European descent, involving 207 taxa.²² The GWAS data for plasma metabolites were obtained from the Canadian Longitudinal Study on Aging cohort, comprising 8,299 participants.²³ This analysis encompassed 1,091 metabolic features and 309 metabolite ratios.

The GWAS data for OSA were obtained from the FinnGen database (R10) with 410385 individuals of European ancestry. The data contained 43901 OSA cases and 366484 controls. OSA diagnostic criteria was depended on ICD codes (ICD-10: G47.3; ICD-9: 3472), which were obtained from the Finnish National Hospital Discharge Registry and the Causes of Death Registry. The ICD-10 code G47.3 encompasses both OSA and central sleep apnea (CSA). Nevertheless, Strausz et al validated the registry-based OSA diagnosis, reporting a positive predictive value of >98%, indicating a high level of diagnostic accuracy.²⁴ The FinnGen study is a large-scale genomics project that has analyzed more than 500,000 Finnish biobank samples, linking genetic variations with health data to uncover disease mechanisms and predispositions.²⁵

Instrumental Variables Selection

In this study, SNPs were selected as IVs, and their selection and validation followed the criteria outlined below. Firstly, due to the limited number of genome-wide significant SNPs available for gut microbiota, we applied a significance threshold of P < 1e-5 to identify potentially relevant SNPs. For the selected mediator metabolites, MR analyses were performed using OSA as the outcome, with SNPs selected based on a stricter threshold of P < 5e-6. Secondly, to minimize bias from linkage disequilibrium (LD), we performed SNP clumping using an LD threshold of R² < 0.001 within a 10,000 kb window. Thirdly, to reduce the risk of weak instrument bias, we calculated the F-statistic for each SNP and retained only those with F > 10 as valid IVs. Functional annotation of SNPs was conducted using functional mapping and gene annotation (FUMA) (Version 1.8.0), based on the most recent release of the GWAS Catalog.²⁶ To reduce the risk of potential pleiotropy, SNPs previously associated with OSA-related traits, such as body mass index, waist circumference, hip circumference, or waist-to-hip ratio, were excluded (Supplementary Table 2).

Statistical Analysis

We conducted a two-sample MR analysis to evaluate the causal relationships between gut microbiota and OSA, as well as between plasma metabolites and OSA independently. We evaluated the causal association between gut microbiota and the plasma metabolites using bidirectional MR. We used the IVW method as the primary MR approach. To enhance the robustness and reliability of our findings, we also applied complementary MR methods, including MR-Egger regression, weighted median, simple mode, and weighted mode. Apart from the MR methods outlined above, we also carried out various supplementary sensitivity analyses. Firstly, we evaluated heterogeneity in causal inference through the calculation of Cochran’s Q statistic. Secondly, we applied the MR-Egger intercept test to detect horizontal pleiotropy. Moreover, the MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) method was employed to detect horizontal pleiotropy and identify potential outlier SNPs. A global test P-value < 0.05 was considered indicative of significant distortion in the causal estimates due to pleiotropy. Additionally, we employed the MR Steiger directionality test to ascertain the causal direction between the exposure and the outcome. Furthermore, the reliability of the findings was assessed through a leave-one-out approach for validation.

Effect sizes were expressed as odds ratios (OR), β-coefficients, and corresponding 95% confidence intervals (CI). All statistical analyses were conducted using the “TwoSampleMR” package (version 0.6.6), “MRPRESSO” package, and “ggplot2” packages within R software (version 4.4.1).

Results

Instrument Variables Included in Analysis

Based on the predefined selection criteria, we identified valid IVs from GWAS summary statistics of gut microbiota and plasma metabolites. Supplementary Tables 3 and 4 provide detailed characteristics of these IVs, including their corresponding F statistics. All included SNPs had F statistics greater than 10, supporting adequate instrument strength.

Effects of Gut Microbiota on Obstructive Sleep Apnea

Using the IVW method, this study identified 4 microbial taxa that were associated with a reduced risk of the OSA, including species Parabacteroides merdae, genus Faecalibacterium, species Faecalibacterium prausnitzii and species Bifidobacterium longum (Table 1). Species Parabacteroides merdae exhibited the most pronounced protective effect (OR = 0.909, 95% CI = 0.828~0.999, P value = 0.047). Species Faecalibacterium prausnitzii and genus Faecalibacterium showed the second strongest protective effects (species Faecalibacterium prausnitzii, OR = 0.921, 95% CI = 0.860~0.986, P value = 0.019; genus Faecalibacterium, OR = 0.923, 95% CI = 0.857~0.994, P value = 0.034). The protective effect of species Bifidobacterium longum was comparatively weaker (OR = 0.930, 95% CI = 0.869~0.997, P value = 0.040).

Table 1 Effects of Gut Microbiota on the Risk of Obstructive Sleep Apnea

Effects of Gut Microbiota on Mediators

Following the established criteria and selection workflow, we identified two candidate mediators, 2-hydroxypalmitate and hyocholate, from the top 10 biologically relevant metabolites. As shown in Table 2 and Supplementary Table 5, species Parabacteroides merdae was positively associated with the levels of 2-hydroxypalmitate (β = 0.254, 95% CI = 0.117~0.391, IVW P value < 0.001, IVW P_FDR value = 0.003). Since MR analyses were performed between the selected microbial taxa and the top 10 metabolites with potential biological significance, FDR correction was applied across these 10 tests using the Benjamini–Hochberg method. After FDR correction, no statistically significant associations were observed between genus Faecalibacterium and 2-hydroxypalmitate, species Faecalibacterium prausnitzii and 2-hydroxypalmitate, or species Bifidobacterium longum and hyocholate.

Table 2 Effects of Gut Microbiota on Mediators

Effects of Selected Mediators on the OSA and Mediation Analysis

Table 3 and Supplementary Table 5, demonstrates that elevated levels of 2-hydroxypalmitate were associated with a reduced risk of OSA (OR = 0.926, 95% CI = 0.865~0.991, P value = 0.027). As presented in Figure 2, through two-step MR analysis, 2-hydroxypalmitate was found to mediate 20.53% of the association between the species Parabacteroides merdae and OSA.

Table 3 Effects of Mediators on Obstructive Sleep Apnea

Figure 2 The 2-hydroxypalmitate mediated the causal effect of species Parabacteroides merdae on OSA. Two-step MR was used to evaluate the mediating role of 2-hydroxypalmitate in the causal pathway linking species Parabacteroides merdae to OSA. The causal effect of species Parabacteroides merdae on 2-hydroxypalmitate, 2-hydroxypalmitate on OSA and species Parabacteroides merdae on OSA were assumed to be β1, β2 and β0, respectively. The proportion of the mediated effect (bold text) was determined by dividing β1× β2 by the total effect (β0). MR estimates were derived from the IVW method in two-sample MR. Abbreviations: OSA, obstructive sleep apnea; MR, mendelian randomization; IVW, inverse variance weighted.

MR Sensitivity Analyses

According to the results presented in Supplementary Table 6, no evidence of heterogeneity was observed, as indicated by Cochran’s Q statistic (all P values > 0.05). Both the MR-Egger intercept test and the MR-PRESSO global test indicated no signs of horizontal pleiotropy, with P values greater than 0.05. In addition, the MR-PRESSO method did not identify any outlier variants. The MR-Steiger directionality test provided no evidence supporting a reverse causal relationship from the OSA to the four protective taxa or to 2-hydroxypalmitate. As shown in Supplementary Figures 1–3, the leave-one-out analysis suggested that certain SNPs may have disproportionately influenced the causal estimates. Based on the overall findings from our sensitivity analyses, the observed associations appear to be relatively robust. Nonetheless, these results should be interpreted with caution.

Discussion

In this study, we performed a comprehensive MR analysis utilizing large-scale GWAS summary data to explore the causal relationships between gut microbiota, plasma metabolites, and OSA. In the Dutch Microbiome Project, species Parabacteroides merdae, genus Faecalibacterium, species Faecalibacterium prausnitzii and species Bifidobacterium longum demonstrated a potential protective association with OSA. This study was exploratory in nature. We included the top 10 metabolites with potential biological significance as candidate mediators. Among them, only 2-hydroxypalmitate was found to mediate the association between species Parabacteroides merdae and OSA, with a mediation proportion of 20.53%.

Species Parabacteroides Merdae and OSA

Species Parabacteroides merdae is a Gram-negative, anaerobic, rod-shaped bacterium commonly found in the human gut microbiota.²⁷ Consistent with our findings, species Parabacteroides merdae retained a strong negative association with OSA.²⁸ The potential protective effect of species Parabacteroides merdae against OSA may be related to its role in alleviating obesity.²⁹ Qiao et al reported that species Parabacteroides merdae significantly attenuated high-fat diet-induced weight gain in mice.³⁰ Given that obesity is a major risk factor for OSA, the beneficial effect of species Parabacteroides merdae on obesity may partially explain its protective role against OSA. Fecal microbiota transplantation has been shown to lower systolic blood pressure (SBP), with increased abundances of species Parabacteroides merdae associated with SBP reduction.³¹ Given that OSA is a known risk factor for hypertension, it is plausible that the SBP-lowering effect of species Parabacteroides merdae may be related to improvements in nocturnal intermittent hypoxia. However, this hypothesis requires further investigation. Evidence linking species Parabacteroides merdae to OSA remains limited. However, further investigation into its potential protective role may help uncover novel therapeutic strategies. Given the complexity of the underlying mechanisms, further research is warranted to identify the key pathways and molecular targets through which species Parabacteroides merdae may influence OSA progression.

2-Hydroxypalmitate and OSA

2-hydroxypalmitate, also known as 2-hydroxyhexadecanoic acid, has emerged as a representative member of the 2-hydroxy fatty acid family.³² These molecules constitute essential structural components of mammalian sphingolipids. Sphingolipids are essential components of cell membranes, particularly abundant in the brain, where they help maintain myelin integrity, facilitate neuronal signaling, and support intercellular communication.³³ Fatty acid 2-hydroxylase (FA2H) catalyzes the biosynthesis of hydroxylated sphingolipids by introducing a hydroxyl group at the α-carbon of long-chain fatty acids.³⁴ FA2H gene mutations are linked to leukodystrophy and spastic paraparesis, highlighting the importance of hydroxylated fatty acid-containing sphingolipids in nervous system function.^35,36 Increasing evidence suggests that alterations in sphingolipid pathways may contribute to the etiopathogenesis of neurodegenerative diseases.³⁷ Parkinson’s disease (PD) is one of the most prevalent neurodegenerative disorders. Sphingolipids play a critical role in various cellular processes involved in the pathogenesis of PD, including mitochondrial function, autophagy, and endosomal trafficking.³⁸ Upper airway obstruction and dysfunction are observed in approximately 24% to 65% of PD patients, primarily attributed to laryngopharyngeal motor impairment.^39,40 This dysfunction reflects a broader impairment of neuromuscular control in the upper airway, characterized by reduced tone in the pharyngeal dilator muscles, impaired coordination of respiratory and swallowing reflexes, and delayed glottic opening.¹⁷ These abnormalities may predispose individuals with PD to the development of OSA, particularly during sleep when compensatory mechanisms are further diminished. Given the essential role of sphingolipids in maintaining neuronal membrane stability and supporting axonal conduction, their dysregulation may plausibly impair the integrity of central or peripheral neural pathways involved in upper airway motor control. However, it must be acknowledged that current evidence directly linking 2-hydroxypalmitate to the regulation of upper airway motor function is limited. Further studies are warranted to clarify this potential association.

However, some studies have suggested that 2-hydroxypalmitate may contribute to the development of OSA. 2-hydroxypalmitate is associated with dyslipidemia, a condition commonly observed in obesity.^41,42 Given that obesity is a major risk factor for OSA, 2-hydroxypalmitate may contribute to the development of OSA through pathways related to fatty acid metabolism. Sullivan et al⁴³ found that vitamin D supplementation was associated with lower 2-hydroxypalmitate levels, while Ayyıldız et al⁴⁴ reported a potential beneficial effect of vitamin D supplementation on the prognosis of mild OSA. These findings are inconsistent with our results. Nonetheless, given the exploratory nature of this study, further research is needed to clarify the role of 2-hydroxypalmitate in OSA pathogenesis.

2-Hydroxypalmitate as a Putative Mediator: Implications and Future Directions

In this study, we identified 2-hydroxypalmitate as a potential mediator of the relationship between species Parabacteroides merdae and the reduced risk of OSA. The mediation analysis demonstrated that 2-hydroxypalmitate accounted for 20.53% of the total effect. In terms of effect size, this proportion represents a moderate mediation effect, comparable to those observed in other microbial-metabolite axes involved in disease progression. For example, prior studies have reported mediation proportions ranging from 6.5% to 25.1% in obesity,⁴⁵ 10.29% to 21.9% in type 2 diabetes,⁴⁶ 11.04% to 15.35% in PD,⁴⁷ 14.62% to 37.48% in chronic airway disease,^48,49 and 8.1% to 22.8% in various cancer types.⁵⁰ These findings suggest that the mediation effect observed in our study falls within a biologically meaningful range and supports the role of 2-hydroxypalmitate as a mediator within the causal pathway from species Parabacteroides merdae to OSA.

Previous studies suggest that species Parabacteroides merdae may reduce the risk of OSA through anti-obesity effects, while 2-hydroxypalmitate may confer protection via sphingolipid metabolism, which modulates upper airway motor function. In our analysis, species Parabacteroides merdae and 2-hydroxypalmitate were positively correlated and both linked to reduced OSA risk, supporting the plausibility of this mediation pathway. Although direct evidence for the regulatory relationship between species Parabacteroides merdae and 2-hydroxypalmitate is currently lacking, our findings suggest a biologically relevant connection that merits further investigation. Overall, this study reveals a gut microbiota-metabolite-OSA pathway and offers new evidence for microbial metabolic mediation in OSA. Given the exploratory nature of this study, future experimental and longitudinal studies are warranted to validate these results and elucidate the underlying mechanisms.

Limitations

This study has several limitations that should be acknowledged. First, the GWAS summary statistics used in our MR analyses were derived exclusively from individuals of European ancestry. As a result, our findings may not be fully generalizable to other populations, given known differences in genetic architecture, LD structure, allele frequencies, and environmental modifiers across ancestries. These population-specific factors could influence both the strength and direction of causal associations, potentially limiting the applicability of our results to non-European groups. To enhance the external validity of microbiota-metabolite-disease mediation frameworks, future studies should incorporate GWAS data from ancestrally diverse cohorts and perform replication analyses across multiple populations. Such efforts are essential to improve the global relevance and translational potential of microbiome-informed causal inference. Second, sleep apnea in the FinnGen study was defined using ICD codes (ICD-10: G47.3; ICD-9: 3472), and individual-level polysomnographic (PSG) data, such as the apnea-hypopnea index, oxygen desaturation index, and sleep architecture, were not available. This limitation precludes accurate confirmation of OSA diagnoses, assessment of disease severity, and identification of clinical subtypes (eg, rapid eye movement-predominant or positional OSA). Notably, ICD-10 code G47.3 includes both OSA and CSA. While Strausz et al²⁴ validated the registry-based OSA definition and reported high diagnostic accuracy, the potential for misclassification remains, particularly due to the inclusion of CSA cases. However, given the low prevalence of CSA⁵¹ and the lack of evidence linking our exposures of interest to CSA risk, any such misclassification is likely nondifferential with respect to exposure. From a statistical perspective, this would tend to bias the effect estimates toward the null, resulting in a conservative estimate of the true causal effect. Future studies incorporating PSG-confirmed, individual-level OSA data are therefore warranted to validate and refine these findings. Third, a relaxed significance threshold (P < 1e-5) was used for SNP selection in the MR analyses to increase the number of valid IVs and improve statistical power. This approach has been adopted in previous MR studies involving complex traits and microbiota-related exposures,^50,52 and is considered acceptable in exploratory settings according to a strategy supported by previous methodological literature.^53–55 However, the use of a relaxed threshold may increase the risk of including weak or pleiotropic IVs. To mitigate this concern, we retained only SNPs with F > 10 to ensure sufficient IVs strength, and excluded those associated with known confounders whenever possible. In addition, the leave-one-out analysis suggested that one or more SNPs might disproportionately influence the causal estimates. Nonetheless, no evidence of heterogeneity (Cochran’s Q statistic) or horizontal pleiotropy (MR-Egger intercept and MR-PRESSO global test) was observed, supporting the robustness of our results. These findings should be interpreted with caution. Future studies using larger GWAS datasets and more advanced MR methods are needed to validate our conclusions. For example, multivariable MR, summary-data-based MR to explore the relationships among genetic variants, exposures, and outcomes,^56,57 and Bayesian co-localization analysis to verify shared causal variants and strengthen causal inference⁵⁸ may offer further insights.

Conclusions

In summary, this study highlights the protective effect of species Parabacteroides merdae against OSA. 2-hydroxypalmitate may act as a partial mediator in the association between species Parabacteroides merdae and OSA. These findings provide novel insights into the mechanisms underlying OSA and suggest potential therapeutic targets, offering promising directions for future research and clinical interventions.

Abbreviations

OSA, Obstructive sleep apnea; MR, Mendelian randomization; IVs, instrumental variables; GWAS, genome-wide association studies; SNPs, single-nucleotide polymorphisms; FDR, false discovery rate; IVW, inverse variance weighted; P_FDR, P values adjusted for false discovery rate; HMDB, Human Metabolome Database; CSA, central sleep apnea; LD, linkage disequilibrium; FUMA, functional mapping and gene annotation; MR-PRESSO, the MR-Pleiotropy Residual Sum and Outlier; OR, odds ratios; CI, confidence intervals; SBP, systolic blood pressure; FA2H, Fatty acid 2-hydroxylase; PD, Parkinson’s disease; PSG, polysomnographic.

Data Sharing Statement

The datasets supporting the conclusions of this article are available in IEU open GWAS project repository (https://www.ebi.ac.uk/gwas/). Details regarding the GWAS on OSA can be accessed through the following link: https://r10.risteys.finngen.fi/endpoints/G6_SLEEPAPNO/.

Ethics Approval and Consent to Participate

All data in this study were derived from publicly accessible GWAS using anonymized summary-level datasets. As this research exclusively analyzed de-identified aggregate data without involving individual participants, sensitive personal information, or commercial interests, ethical approval was formally waived by the Ethics Committee of Beijing Friendship Hospital, Capital Medical University (Approval No.: 2025-P2-115). This study was conducted in full compliance with the Declaration of Helsinki and relevant national ethical regulations.

Acknowledgments

We extend our sincere gratitude to the authors and participants of all GWAS studies whose summary statistics data were utilized in this research.

Author Contributions

Xiaona Wang: Conceptualization, Data Curation, Formal analysis, Funding acquisition, Investigation, Methodology, Software, Validation, and Writing – original draft. Ranran Zhao, Jia Guo, and Ke Yang: Data Curation, Formal analysis, Investigation, Methodology, Validation, and Writing – review & editing. Bo Xu: Conceptualization, Funding acquisition, Methodology, Project administration, Resources, Software, Supervision, and Writing – review & editing. All authors made significant contributions to the study, approved the final manuscript for submission, agreed on the choice of journal, and take full responsibility for the integrity of the work.

Funding

This work was supported by the Capital’s Funds for Health Improvement and Research (2024-2-1101 20240402105353, China) and the Seed Program of Beijing Friendship Hospital (YYZZ202235).

Disclosure

The authors declare that they have no competing interests.

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Is reducing the risk of eating disorders with single session interventions a hype or a promise? Tracey Wade at the Flinders University Institute for Mental Health and Wellbeing investigates

What is a single session intervention?

Single session interventions (SSIs) are brief, structured, goal-oriented programs, following evidence-based approaches to create meaningful change to mental health in a single encounter.

What evidence supports SSIs?

An umbrella review of 24 systematic reviews and meta-analyses of SSIs was published between 2007 and 2024. ⁽¹⁾ Only seven included trials of digital or paper-based self-guided SSIs; the remainder focused on face-to-face interactions. Overall, SSIs showed a small, significant positive effect across outcomes and age groups.

Compared to anxiety, depression and substance use, the evidence supporting SSIs for disordered eating is sparse: only two of the systematic reviews included in the umbrella review included studies evaluating eating problems, and only one reported positive effects in adolescents and adults.

What is the rationale for use in the prevention of eating disorders?

So far, insufficient evidence exists to support the use of unguided digital SSIs in the prevention of disordered eating. The rationale for further investigation, however, does exist, as shown in the Figure. Significantly, SSIs may successfully decrease dietary restriction, a key risk factor for the development of disordered eating. Dietary restriction refers to consciously trying to cut back the overall amount eaten to influence shape or weight.

Two studies show a decrease in dietary restriction after completing a SSI. One showed a reduction in restrictive eating in depressed adolescents at three-month follow-up compared to a control condition when either completing a SSI on Behavioural Activation (doing activities that are considered pleasant or display some mastery) or an introduction to the brain and a lesson on neuroplasticity. ⁽²⁾ The second showed a decrease in dietary restriction in adults (mean age of 27.99 years) seeking treatment for an eating disorder, using adapted versions of the two SSIs from the previous study ⁽³⁾ (shown in figure 1).

What questions need to be answered?

A variety of questions that need to be addressed in terms of the usefulness of SSIs for the prevention of eating disorders are listed in table 1. ^(4,5)

Our current research

Our research, funded by a National Mental Health and Research Council Investigator Grant (2025665), has developed nine SSIs on a smartphone app. We consulted young people and members of our Expert Advisory Group (people with lived experience, significant others, and clinicians and researchers specialising in eating disorders) to ensure that the content and features were as engaging as possible. ⁽⁶⁾

Young people aged 14–25 years old with elevated weight concern will be randomised to one of nine SSIs tackling risk factors for disordered eating or a control condition. The content of each SSI is described below. This important research will help better understand the role SSIs can play in reducing the risk of eating disorders in youth.

References

1. Schleider JL, Zapata JP, Rapoport A., et al. (2025). Single-Session Interventions for Mental Health Problems and Service Engagement: Umbrella Review of Systematic Reviews and Meta-Analyses. Annual Review of Clinical Psychology, 21(1), 279–303.
2. Schleider JL., Mullarkey MC, Fox KR, et al. (2022). A randomized trial of online single-session interventions for adolescent depression during COVID-19. Nature Human Behaviour, 6(2), 258–268.
3. Wade TD, Waller G. (2025). Transdiagnostic single session interventions identify rapid versus gradual responders and inform therapy personalisation before commencing therapy for eating disorders. Cognitive Behaviour Therapy.
4. O’Dea B & de Valle MK. (2025). Trial, Error, and Insight: Using the Pilot Study of the HOPE Program to Inform Next Steps for Digital Single-Session Research for Eating Disorders. International Journal of Eating Disorders, 10.1002/eat.24487.
5. Thompson M, Radunz M, Wade TD, Balzan RP. (2024). Bridging the gap: Can single session interventions help enhance mental health treatment delivery for young people in Australia? Australian & New Zealand Journal of Psychiatry, 58(10):829-830.
6. Pellizzer ML, Pennesi J-L, Radunz M, Zhou Y, Wade TD. (2025). Piloting single session interventions in a sample of weight-concerned youth: Study protocol for a randomised controlled trial. Body Image, 54, 101945.

The sixth edition of the European Research and Innovation (R&I) Days will take place on 16-17 September 2025 at The Square in Brussels, bringing together key players from across Europe’s research, business, and innovation

Organised by the European Commission, this event will help to shape the future of EU research by fostering dialogue, collaboration, and solutions in areas critical to Europe’s competitiveness and sustainability.

Among the highlights of the 2025 edition will be three groundbreaking projects managed by the European Health and Digital Executive Agency (HaDEA). These projects, funded under the Horizon 2020 programme, focus on advancing research in health, digital innovation, and environmental sustainability, key priorities for the EU’s future.

MAESTRIA: Advancing heart health through AI

A significant project featured at the event is MAESTRIA (Machine Learning Artificial Intelligence Early Detection of Stroke and Atrial Fibrillation). This project is transforming how medical professionals detect and manage atrial cardiomyopathy, a heart condition associated with atrial fibrillation (AF) and stroke.

By combining advanced AI algorithms, medical imaging, and cutting-edge research, MAESTRIA is building the first-ever digital diagnostic platform specifically for atrial cardiomyopathy. The goal is to enable personalised diagnosis, better risk assessment, and more effective treatment options, ultimately reducing complications like AF and stroke.

The project represents a significant leap forward in preventive healthcare, offering scalable tools to enhance patient outcomes and alleviate the burden of cardiovascular disease across Europe.

PERSEPHONE: Robotics for sustainable seep mining

In terms of industrial innovation, PERSEPHONE (Autonomous Exploration and Extraction of Deep Mineral Deposits) is leading efforts to modernise and automate deep mining operations. As demand for raw materials critical to the green and digital transitions grows, Europe is turning to more brilliant, safer, and more sustainable ways to access these resources.

PERSEPHONE is developing compact, energy-efficient autonomous robots capable of exploring deep or abandoned mines. These robotic systems are equipped with sensors and cameras that generate 3D scans of underground environments. The data collected is used to create a digital twin of the mine, enabling precise planning for safe and efficient mineral extraction.

By minimising risks to human workers and reducing environmental impact, PERSEPHONE supports the EU’s efforts to build a resilient supply chain for critical raw materials, essential for clean energy technologies and digital innovation.

eMOTIONAL cities: Designing healthier urban spaces

Another innovative project, eMOTIONAL Cities, recently concluded its mission to understand how urban environments affect people’s emotional and mental well-being. Using a unique device known as the Cities walker backpack, the project gathered real-life biometric data to assess how individuals respond emotionally to different urban settings.

The findings from eMOTIONAL Cities offer valuable insights for urban planners and policymakers aiming to create healthier, more inclusive cities. By linking emotional responses to environmental factors, the project contributes to the design of urban spaces that promote calmness, happiness, and social connection.

R&I days 2025

Attendees of R&I Days 2025 will have the chance to explore these projects in the exhibition area, engage in high-level discussions, and participate in networking opportunities with policymakers, researchers, and innovators.

This year’s event highlights how EU-funded research, under programmes such as Horizon 2020 and Horizon Europe, continues to drive forward solutions in health, digitalisation, and sustainability, paving the way for a stronger, more resilient Europe.

The American Cancer Society (ACS) has published its annual Prostate Cancer Statistics, 2025 report, showing increasing incidence rates alongside slowing declines in mortality rates.¹

Data for the report were collected by the National Cancer Institute and the Centers for Disease Control and Prevention. Population-based incidence data were analyzed through 2021, and mortality data were analyzed through 2023.

Trends in Incidence and Mortality

Overall, the data showed a marked reversal in prostate cancer incidence trends in recent years. Although the incidence rates declined by 6.4% per year from 2007 to 2014, data show that these rates have been increasing by 3.0% annually from 2014 to 2021. This trend has been largely driven by increasing rates of advanced-stages diagnoses, which are climbing by approximately 4.6% to 4.8% per year.

Notably, prostate cancer mortality rates have been decreasing since the 1990s, though the declines have slowed in recent years. In the 1990s and 2000s, mortality rates decreased by 3% to 4% annually. Over the past decade, these rates have waned to approximately 0.6% per year.

According to the report, rates of distant-stage disease are increasing across every age group. Specifically, rates are increasing by about 3% in those younger than 55 years and about 6% among those aged 55 years and older.

The 5-year relative survival rate for distant-stage prostate cancer is 38%, but the rate increases to nearly 100% for men diagnosed with local-stage or regional-stage disease, emphasizing the importance of early detection.

Overall, the ACS estimates that in 2025, there will be 313,780 new cases of prostate cancer and 35,770 deaths due to the disease.

Persistent Disparities

The report also sheds light on persistent and wide racial disparities.

Based on the data, Black men have a 67% higher incidence rate and are 2 times more likely to die from prostate cancer compared with White men. Similarly, Native American men have a 12% higher prostate cancer mortality rate compared with White men, despite having a 13% lower incidence rate.

“Our research highlighting the continued increases in prostate cancer incidence and persistent racial disparities underscores the need for redoubled efforts to understand the etiology of prostate cancer and optimize early detection,” commented lead author Tyler Kratzer, MPH, associate scientist, cancer surveillance research at the ACS, in a news release from the organization.² “At age 50, per ACS guidelines, all men should have a conversation with their health care provider about the benefits and harms of screening, but Black men and those with a family history of prostate cancer should have that conversation at age 45.”

Data also showed that American Indian and Alaska Native (AIAN) men were the most likely racial group to be diagnosed with distant-stage disease (12% vs 8% among White men). According to the authors, this finding “at least in part reflect[s] lower screening prevalence compared with other men.”

Further, data showed that prostate cancer mortality rates are highest among Black men at 36.9 per 100,000 population, following by 20.6 deaths per 100,000 among AIAN men, 18.4 deaths per 100,000 among White men, 15.4 deaths per 100,000 among Hispanic men, and 8.8 deaths per 100,000 among Asian American and Pacific Islander men.

By geographic location, the highest prostate cancer mortality rates were observed in Washington DC (27.5 deaths per 100,000 population) and Mississippi (24.8 deaths per 100,000 population), both of which have a high proportion of Black residents.

The authors noted, “Increases in advanced diagnosis and persistent disparities highlight the need for redoubled efforts to optimize early detection and address barriers to equitable outcomes, including improved access to high-quality health care for all men.”

Ongoing Legislative Efforts

The Prostate-Specific Antigen Screening (PSA) for High-risk Insured Men (HIM) Act (H.R. 1300/S. 297) is a bipartisan bill in Congress aimed at improving access to prostate cancer screening. Specifically, this bill would waive cost-sharing requirements (deductibles, copays, and coinsurance) for prostate cancer screening tests for men who are at high-risk for the disease.

The ACS Cancer Action Network, the advocacy affiliate for the ACS, has expressed strong support for the bill.

“Out-of-pocket costs such as co-pays can be a barrier to accessing early detection,” explained Lisa A. Lacasse, president of ACS CAN, in the news release.² “No one should be at a disadvantage against cancer. The PSA Screening for HIM Act will help remove a major obstacle that can prevent those at high risk for the disease from getting the screening tests they need to find prostate cancer at the earliest, most treatable stage.”

She added, “We urge the House and the Senate to pass this legislation to help reduce prostate cancer disparities and save more lives.”

REFERENCES

1. Kratzer TB, Mazzitelli N, Star J, et al. Prostate cancer statistics, 2025. CA: A Cancer Journal for Clinicians. 2025. doi:10.3322/caac.70028

2. New ACS Prostate Cancer Statistics Report: Late-stage incidence rates continue to increase rapidly as mortality declines slow. News release. American Cancer Society. September 2, 2025. Accessed September 2, 2025. https://www.prnewswire.com/news-releases/new-acs-prostate-cancer-statistics-report-late-stage-incidence-rates-continue-to-increase-rapidly-as-mortality-declines-slow-302543895.html

The joint project began when a nine-year-old boy came to Prof. Shoshana Greenberger’s clinic at Sheba’s Safra Children’s Hospital with severe shortness of breath and was diagnosed with KLA. Seeking to deepen understanding of the disease, Greenberger approached Prof. Karina Yaniv, of Weizmann’s Immunology and Regenerative Biology Department, who for over two decades has been studying how blood and lymphatic vessels form, using zebrafish models.

In KLA, lymphatic vessels become abnormally enlarged and distorted, which keeps the lymphatic system from properly doing its job: draining fluid from tissues and supporting many essential bodily functions. As in the case of the boy treated by Greenberger, what typically brings young patients to the doctor is difficulty breathing caused by fluid buildup in the chest, but the disease also affects the skin and numerous other organs

“It was an amazing moment. Just by looking at these mutant embryos, I knew we were on the right track”

In earlier work led by Greenberger, her team at Sheba had traced the disease to a single mutation in a gene called NRAS, known to act as an oncogene. Physicians around the world started treating patients with certain cancer drugs that block NRAS or its partners, but these drugs are not always sufficiently effective and they come with harsh side effects. They failed to save the life of Greenberger’s patient, but the boy’s cells became the basis of research into the mechanisms of KLA.

“We wanted to be sure the mutation we had found really causes KLA and learn how it does that, in the hope of finding a better therapy,” says Greenberger, who heads the Multidisciplinary Center for Vascular Anomalies at Sheba. “That’s what led us to the collaboration with Weizmann.”

Zebrafish became powerful allies in this research not only because their embryos are transparent and develop rapidly, but also because their lymphatic systems share a surprising number of features with those of humans, from genetics to anatomy. The project – jointly spearheaded by Greenberger and Yaniv and led by Dr. Ivan Bassi, a postdoctoral fellow in Yaniv’s lab – began with creating a zebrafish model of the human disease. This model was initially validated by Amani Jabali, an MSc student supervised by Greenberger and Yaniv.

Since the human NRAS gene is about 80 percent identical to the zebrafish version and activates similar biochemical pathways, the researchers were able to insert the mutated human gene, taken from the cells of Greenberger’s patient, into tiny zebrafish embryos. The challenge was to ensure that the mutated gene was expressed in the lymphatic vessels alone, as it is in human disease, and nowhere else in the body. Once this was achieved, the embryos developed lymphatic abnormalities that bore a remarkable resemblance to those of human patients.

“It was an amazing moment,” Yaniv recalls. “Just by looking at these mutant embryos, I knew we were on the right track.”

The main lymphatic vessel of the embryos became grossly distorted, causing their hearts to become dilated and balloon. Further examination confirmed that these embryos shared key features with human KLA patients, including enlarged lymphatic vessels and swelling around the heart.

Using their model, Bassi and colleagues deciphered previously unknown aspects of the disease mechanism. In healthy cells, NRAS triggers cell division only when activated by a signal. In KLA, the mutated NRAS is stuck in the “on” position, causing lymphatic cells to divide and grow uncontrollably.   

Hooked on discovery

The next critical step was finding a small molecule that could block the effects of the disease-causing mutation. Zebrafish embryos were perfect for this task because they enabled the testing of potential drugs on a living organism, not just isolated proteins or cells. But they also posed a major headache. High-throughput screening, the standard method for quickly testing large numbers of compounds, is normally automated. The tricky part was figuring out how to get each zebrafish into exactly the right position under a microscope – without doing it by hand – so that a machine could capture consistent images and assess the effects of treatments.

Working with collaborators, the team designed a clever automated system, in which each embryo was gently dropped into a precisely fitting slit under the microscope, where it was photographed. Then, an AI-based algorithm outlined the entire body of the larval fish and measured its area after exposure to each drug. Because the mutant fish had enlarged hearts, their total body area was significantly greater than normal, an effect expected to decrease after treatment with an effective drug.

Using this setup, the team screened about 150 small molecules, all of them existing drugs already approved for other uses. About 30 showed promising effects; two top candidates were ultimately selected through further testing.

Both these drugs reversed the KLA-like symptoms in the zebrafish model: The ballooned heart and main lymphatic vessel shrank back to their normal size and shape. To test whether these drugs might help treat the human disease, the Sheba team applied them to lymphatic cells from Greenberger’s KLA patient. The two compounds had a striking effect, blocking the cells’ abnormal sprouting, a hallmark of the disease. Importantly, both drugs have a better safety profile than the cancer drugs physicians use today to treat KLA, meaning they could cause fewer side effects.

“We hope a clinical trial will be launched soon to evaluate these drugs in patients,” Greenberger says. “Since KLA is a rare disease, we will work toward creating a multi-center collaboration to bring together enough participants.”

Meanwhile, Yaniv’s lab is using zebrafish models to explore other lymphatic disorders and to further investigate KLA. One question still puzzles them: Why does the NRAS mutation severely damage lymphatic vessels but leave veins and arteries untouched? Solving this mystery could lead to entirely new therapeutic strategies.

“These are longer-term questions,” Yaniv says, “but what we’ve found in the present study could help patients much sooner. Since the drugs we identified are already approved, getting them repurposed for KLA could move much faster than starting from scratch.”

Reference: Bassi I, Jabali A, Levin L, et al. A high-throughput zebrafish screen identifies novel candidate treatments for kaposiform lymphangiomatosis (KLA). J Exp Med. 2025;222(11):e20240513. doi: 10.1084/jem.20240513

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