Int J Med Sci 2025; 22(14):3565-3580. doi:10.7150/ijms.115853 This issue Cite

Research Paper

Causal Effects of Exposure to Air Pollution on the Risk of Neurosurgical Multi-system Diseases: A Worldwide Study of Mendelian Randomization

Lirui Dai, Shu Jiang, Peizhi Zhou Corresponding address

Department of Neurosurgery, West China Hospital of Sichuan University, Sichuan University, Chengdu, Sichuan, China.

Received 2025-4-16; Accepted 2025-7-16; Published 2025-7-28

Citation:
Dai L, Jiang S, Zhou P. Causal Effects of Exposure to Air Pollution on the Risk of Neurosurgical Multi-system Diseases: A Worldwide Study of Mendelian Randomization. Int J Med Sci 2025; 22(14):3565-3580. doi:10.7150/ijms.115853. https://www.medsci.org/v22p3565.htm
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Abstract

Graphic abstract

Background: Epidemiological studies has investigated the correlation between ambient air pollution and neurosurgical multisystem diseases. Multiple studies have shown that air pollution significantly influences various neurological disorders. Nevertheless, the findings from these studies are inconsistent and contentious, leaving the causal relationships for many conditions unresolved. The study systematically investigates the underlying genetic causal relationships between air pollution and neurosurgical multisystem diseases, as well as to assess the implications of these associations.

Methods: Genetic instruments for particulate matter (PM) with aerodynamic diameter < 2.5 μm (PM2.5), < 2.5-10 μm (PM2.5-10), <10 μm (PM10), PM2.5 absorbance, nitrogen dioxide (NO2), nitrogen oxides (NOx) and 30 neurosurgical multi-system diseases were selected.

Results: In the European population, a noteworthy causal association was identified between NO2 and PM2.5 exposure and cerebral infarction (IVW: OR = 1.03, 95%CI: 1.01~1.06). Among African American or Afro-Caribbean individuals, NOx (IVW: OR = 0.63, 95%CI: 0.44~0.90) and NO2 (IVW: OR = 0.68, 95%CI: 0.54-0.87) are predisposed to trigger trigeminal neuralgia, while PM2.5 is related to 3 neurosurgical diseases, including epilepsy (IVW: OR = 0.89, 95%CI: 0.79~1.00), subarachnoid hemorrhage (IVW: OR = 0.75, 95%CI: 0.61~0.91), and diffuse brain injury (IVW: OR = 0.67, 95%CI: 0.47~0.96). In East Asian populations, a correlation has been observed between PM2.5 (IVW: OR = 0.99, 95%CI: 0.98~1.00) and PM10 (IVW: OR = 1.00, 95%CI: 1.00~1.00) exposure and the occurrence of cervical spondylosis. Additionally, there is a genetic susceptibility to pituitary adenoma and craniopharyngioma related to NO2 (IVW: OR = 1.24, 95%CI: 1.02~1.52) and PM2.5 absorbance (IVW: OR = 0.73, 95%CI: 0.59~0.90). In South Asian populations, there is a significant genetic susceptibility to the influences of PM2.5-10 (IVW: OR = 0.90, 95%CI: 0.83~0.97) on stroke incidence. In contrast, for populations in the Greater Middle East, air pollution is predominantly associated with cerebrovascular diseases. For example, PM2.5-10 shows a positive genetic predisposition towards stroke (IVW: OR = 1.02, 95%CI: 1.00~1.05) and subarachnoid hemorrhage (IVW: OR = 1.06, 95%CI: 1.00~1.12).

Conclusion: This study presents the first genetic evidence establishing a connection between air pollution and neurosurgical multisystem diseases. Our findings emphasize the importance of air quality in the context of these diseases, potentially offering new insights into the underlying mechanisms and informing future clinical research on air pollution-mediated neurosurgical conditions, particularly cerebrovascular and brain functional disorders.

Keywords: air pollution, neurosurgical multi-system diseases, Mendelian randomization, genetic associations

1. Introduction

Emerging evidence suggests that ambient air pollution, comprising complex mixtures of various PM and NOx [1], poses multiple adverse hazards to human health and may elevate the morbidity and mortality rates of cardiovascular, cerebrovascular, and oncological diseases [2, 3]. Studies have showed that air pollution can enhance the risk of mortality from non-communicable diseases by nearly 20% [2]. Notably, air pollution and the occurrence of neurosurgical multisystem diseases has underlying correlation. The neurosurgical multisystem diseases here are classified into five major categories based on clinical experience, including functional diseases, cerebrovascular diseases, Spinal and spinal cord diseases, central nervous system neoplasms and Other brain diseases, which facilitates our summary of the relationship between different types of neurosurgical diseases and environmental pollution (Details in Figure 1). Since the 1990s, epidemiological data from multiple research teams across North America, Asia, and Europe have demonstrated a correlation between air pollution and cerebrovascular disease mortality. Regions with elevated gaseous pollutants, including PM2.5 and ozone, have experienced a significant increase in cerebrovascular accidents [4]. Furthermore, numerous studies have also explored the influence of air pollution on other neurological disorders. For example, Shreya Louis et al. found that epilepsy is closely associated with air pollution and temperature, while long-term and short-term exposure to air pollution, such as PM2.5, PM10, PM2.5-10 and NOx were significantly associated with ischemic stroke and transient ischemic attack [3]. Ma et al. discovered that prolonged exposure to high concentrations of PM2.5 can lead to the accumulation of amyloid protein, thereby heightening the risk of cognitive impairment and influencing the neurobiological characteristics associated with Alzheimer's disease [5]. Additionally, study has indicated that exposure to air pollution is relevant to increase of risk both benign [6] and malignant brain tumors [7]. However, further investigation is required to elucidate the specific types of tumors involved and the underlying mechanisms of their development.

Therefore, the influence of ambient air pollution on neurosurgical multi-system diseases cannot be ignored [8-10], and these pollutants bring a heavy burden to the human body and aggravate the comorbidities [11]. Nowadays, many prospective studies and epidemiological investigations have displayed that air pollution is highly relevant to a variety of neurological diseases, such as stroke [12], Alzheimer's disease [13], Parkinson's disease [14] and epilepsy [15]. Due to the regional or population-specific focus of these studies, rather than utilizing a diverse array of clinical samples across various races and regions, the findings are subject to confounding factors and lack systematic generalizability. The aim of this study is to systematically survey the correlation between neurosurgical multi-system diseases and air pollution across different races and populations using Mendelian randomization analysis. Furthermore, it seeks to comprehensively summarize the impact of air pollution on neurological diseases, and provide research basis for guiding neurosurgeons to treat related diseases and local governments to control air pollution.

Our study indicates that genetic polymorphisms can enhance our comprehension of environmental health risks. To address the aforementioned methodological challenges, we utilized Mendelian randomization (MR) analysis [16]. The MR approach, grounded in Mendel's second law of inheritance to mitigate confounding factors [17], utilizes genetic variation as instrumental variables (IVs) to evaluate the correlation between air pollution and neurosurgical multisystem diseases. We proceeded the two-sample MR analysis applying data from genome-wide association studies (GWAS) [18]and UK Biobank [19] data in this research. It is noteworthy that, in recent years, numerous researchers have employed MR techniques to probe underlying relationships between ambient air pollution and various tumors [7], adverse pregnancy [20], cardiovascular disease [21], autoimmune disease [22], chronic obstructive pulmonary disease [23], cognitive ability [24], and amyotrophic lateral sclerosis [25]. However, to date, no researchers have applied MR methods to study the effects of air pollution on neurological diseases.

Therefore, this study aims to utilize comprehensive data on ambient air pollution and neurosurgical multisystem diseases to elucidate their causal relationship, thereby informing strategies to mitigate the influence of air pollution on neurological conditions through public health prevention and intervention measures.

2. Methods

2.1. Overall research design

Figure 1 elucidates the whole study design. We adopted MR analysis to survey the causal correlation between ambient air pollution and neurosurgical multisystem diseases. The study followed strictly to the STROBE-MR guidelines [26] and was meticulously designed based on three key hypotheses, including: 1. The IVs in this study are genetic variations closely related to ambient air pollution, specifically SNPs. 2. These genetic variations are not relevant to confounding variables and influence disease outcomes solely through the specific exposure under investigation. 3. The genetic variants impact neurological diseases exclusively via ambient air pollution, without involvement of alternative pathways [27]. Previous studies have confirmed that particulate matter and nitrogen oxides can directly damage the central nervous system by disrupting the blood-brain barrier, causing neuroinflammation and oxidative stress [28]. Therefore, this study mainly selected PM2.5, PM2.5-10, PM10, PM2.5 absorbance, NO2 and NOx for in-depth research. For O₃ and SO₂, due to significant data gaps in O₃ monitoring and a notable decrease in SO₂ concentration in recent years, which limited the epidemiological association analysis, they were not included in this study. The diseases discussed in this study include 30 neurological diseases.

2.2. Summary datasets and populations

We obtained ambient air pollution via IEU Open GWAS (https://gwas.mrcieu.ac.uk/) [29] database as exposure factors for populations of European, African American or Afro-Caribbean, South Asian, East Asian, and Greater Middle Eastern. Ambient air pollution is caused by various air pollution, such as PM2.5, PM10, PM2.5-10, NOx, suspended particles (TSP), carbon oxides (CO, CO2), hydrocarbons (CH4) and other harmful substances [30]. Since the 1990s, PM2.5 is the most widely studied air pollution, followed by nitrogen oxides such as NO2 and NOx [31]. In recent years, particles with an aerodynamic diameter of 2.5 to 10μm are also receiving increasing attention, and different pollution have different degrees of damage to human health [32]. Based on this, we selected the above pollutants as the main exposure factors for MR analysis (Fig.2).

 Figure 1 

The flow chart of the MR analysis and study design. A. MR assumption. 1. SNPs are not associated with confounder; 2. SNPs are strongly associated with air pollution; 3. SNPs influence neurosurgical multi-system diseases solely through air pollution. B. Analysis flow chart.

Int J Med Sci Image

The GWAS database from Neale's lab provides the source of data on neurosurgical multisystem disorders, including Trigeminal neuralgia (195,847 cases), Epilepsy (458,310 cases), Parkinson's disease (480,018 cases), Alzheimer's disease (487,511 cases), Major depressive disorder (56,637 cases), Obsessive compulsive disorder (33,925 cases), Stroke (446,696 cases), Intracerebral hemorrhage (473,513 cases), Subarachnoid hemorrhage (473,255 cases), Transient ischemic attack (214,634 cases), Cerebral infarction (361,194 cases), Cerebral aneurysm (473,683 cases), Cervical spondylosis (484,598 cases), Spinal canal stenosis (454,787), Spinal meningioma (218,792 cases), Spinal osteochondrosis (164,865 cases), Intracranial and intraspinal abscess (217,626 cases), Cervical spinal cord and nerve injuries (215,730 cases), Glioblastoma (218,792 cases), Benign meningioma (218,792 cases), Malignant meningioma (218,792 cases), Pituitary adenoma and craniopharyngioma (218,792 cases), Benign neoplasm of brain and other parts of CNS (218,792 cases), Malignant neoplasm of brain and other parts of CNS (218,792 cases), Hydrocephalus (206,548 cases), Craniosynostosis (218,792 cases), Concussion (147,103), Diffuse brain injury (137,232 cases), Focal brain injury (137,641 cases) and Congenital malformations of the nervous system (218,792 cases) (Table 1). The above diseases in each major category are all common in clinical practice and also the most frequently encountered diseases in our daily operations in neurosurgery or in collaboration with the neurology department.

2.3. Selection of SNPs

To ascertain that ambient air pollution possesses a sufficient number of IVs to maintain statistical efficacy and meet the three hypothesis of MR analysis, we chose SNPs that demonstrated a strong relevance to air pollution (p<1e-5) (Table S1-S28). We employed thresholds of R²<0.001 and a distance greater than 10,000Kb to evaluate, identify, and exclude linkage disequilibrium (LD) effects, thereby ensuring the independence of the IVs. To mitigate the potential for horizontal pleiotropy and eliminate confounding variables, we utilized the PhenoScanner V2 database (http://www.phenoscanner) [33]. In addition, our choice of IVs also excluded palindromic SNPs to guarantee that the influences on exposure and outcomes correspond to the same alleles. To satisfy another assumption of MR analysis, we utilized the coefficient of determination (R²) as a genetic instrument to quantify the proportion of variance explained for traits, calculated as R² =2MAF×(1-MAF) (β / SD)². The F statistic was employed to assess the existence of weak IV bias and to determine the stability of individual SNPs. When F>10, SNPs are deemed to be undisturbed by weak IV bias, manifesting that the selected SNPs can precisely forecast exposure. The formula is as follows: F= [(K+1-N) R2] / [K(R2-1)]) [34]. K: variants, N: sample size (Fig.1).

2.4. Statistical analysis

In this study, inverse variance weighting (IVW) was primarily applied to estimate the relevance between air pollution and neurosurgical multi-system diseases, with weighted median (WM) and MR-Egger methods employed to further assess this correlation [35]. Sensitivity analyses incorporated heterogeneity analysis, horizontal pleiotropy analysis, and leave-one-out analysis. Cochran's Q statistic was applied to evaluate the heterogeneity of each MR association. P<0.05 for Cochran's Q statistic indicates heterogeneity exists, necessitating the use of a random effects model as the major method for subsequent testing [36]. MR-PRESSO method was assessed using MR-PRESSO outlier tests, corrected level pleiotropy (outlier test), and remarkable discrepancy in causal estimates before and after outlier adjustments [35]. Subsequently, a leave-one-out analysis was conducted to assess whether individual SNPs yielded remarkable consequences, thereby systematically excluding confounding SNPs [37]. Statistical analyses were proceeded applying R version 4.2.0 and the TwoSampleMR package version 0.6.3. A strong correlation was established when the results remained significant after applying the Bonferroni correction [38]. Furthermore, a strong correlation was deemed present if more than two distinct MR analyses yielded P-values less than 0.05. Even in cases where only a single method, particularly the IVW analysis, produced a P<0.05, the correlation was still deemed remarkable.

3. Results

3.1. MR analysis

To survey the relationship between ambient air pollution and neurosurgical multisystem diseases, we carried out the first global-scale MR analysis. Based on the variations in ambient air pollution, we proceeded with the subsequent analyses.

3.2. Causal effects of NOx on neurosurgical multisystem diseases

In the initial IVW, WM, and MR-Egger analyses, we utilized closely related SNPs as genetic instruments for investigating neurosurgical multisystem diseases (Fig.3 and Fig.4). Our consequences revealed a positive relativity between NOx and the dangerousness of spinal meningioma, and a negative relevance with the risk of major depressive disorder in the European population. NOx is negatively associated with the dangerousness of trigeminal neuralgia and cerebral aneurysm in African American or Afro-Caribbean population. NOx is positively correlation with the risk of focal brain injury in South Asian. And NOx is positively correlation with the risk of malignant neoplasm of brain and other parts of CNS in East Asian. However, no causal correlation has been discovered between NOx and other neurosurgical disorders in other populations (Fig.3, Fig.4 and Table S1-S5).

 Table 1 

Details of GWAS in the present study (outcome).

CharacteristicsConsortiumGWAS IDSample sizeNumber of SNPsPopulationSexYear
Neurosurgical disordersDiseases
functional diseasesTrigeminal neuralgiaNAfinn-b-G6_TRINEU195,84716,380,408EuropeanMales and females2021
EpilepsyNAebi-a-GCST90018840458,31024,186,492EuropeanNA2021
Parkinson's diseaseNAebi-a-GCST90018894480,01824,194,622EuropeanNA2021
Alzheimer's diseaseNAebi-a-GCST90027158487,51120,921,626EuropeanNA2022
Major depressive disorderNAebi-a-GCST9008605956,63711,498,420EuropeanNA2021
Obsessive Compulsive DisorderPGCieu-a-118933,9258,409,517EuropeanMales and females2017
cerebrovascular diseasesStrokeNAebi-a-GCST005838446,6967,633,440EuropeanNA2018
Intracerebral hemorrhageNAebi-a-GCST90018870473,51324,191,284EuropeanNA2021
Subarachnoid hemorrhageNAebi-a-GCST90018923473,25524,191,735EuropeanNA2021
Transient ischemic attackNAfinn-b-G6_TIA214,63416,380,437EuropeanMales and females2021
Cerebral infarctionNAukb-d-I63361,19410,889,323EuropeanMales and females2018
Cerebral aneurysmNAebi-a-GCST90018815473,68324,191,145EuropeanNA2021
Spinal and spinal cord diseasesCervical spondylosisNAebi-a-GCST90038693484,5989,587,836EuropeanNA2021
Spinal canal stenosisNAebi-a-GCST90018922454,78724,182,979EuropeanNA2021
Spinal meningiomaNAfinn-b-CD2_BENIGN_MENINGES_SPINAL218,79216,380,466EuropeanMales and females2021
Spinal osteochondrosisNAfinn-b-M13_SPINALOSTEOCHON164,86516,380,216EuropeanMales and females2021
Intracranial and intraspinal abscessNAfinn-b-G6_CNSABSC217,62616,380,461EuropeanMales and females2021
Cervical spinal cord and nerve injuriesNAfinn-b-ST19_INJURY_NERVES_SPINAL_CORD_NECK_LEVEL215,73016,380,463EuropeanMales and females2021
central nervous system neoplasmsGlioblastomaNAfinn-b-C3_GBM218,79216,380,466EuropeanMales and females2021
Benign meningiomaNAfinn-b-CD2_BENIGN_MENINGES_CEREBRAL218,79216,380,466EuropeanMales and females2021
Malignant meningiomaNAfinn-b-C3_MENINGES218,79216,380,466EuropeanMales and females2021
Pituitary adenoma and craniopharyngiomaNAfinn-b-CD2_BENIGN_PITUITARY_CRANIPHAR218,79216,380,466EuropeanMales and females2021
Benign neoplasm of brain and other parts of CNSNAfinn-b-CD2_BENIGN_BRAIN_CNS218,79216,380,466EuropeanMales and females2021
Malignant neoplasm of brain and other parts of CNSNAfinn-b-C3_SPINAL_CORD_CRANIAL_AND_OTHER_CNS218,79216,380,466EuropeanMales and females2021
Other brain diseasesHydrocephalusNAfinn-b-G6_HYDROCEPH206,54816,380,404EuropeanMales and females2021
CraniosynostosisNAfinn-b-Q17_CRANIOSYNOSTOSIS218,79216,380,466EuropeanMales and females2021
ConcussionNAfinn-b-ST19_CONCUSSION147,10316,380,074EuropeanMales and females2021
Diffuse brain injuryNAfinn-b-ST19_DIFFU_BRAIN_INJURY137,23216,379,965EuropeanMales and females2021
Focal brain injuryNAfinn-b-ST19_FOCAL_BRAIN_INJURY137,64116,379,970EuropeanMales and females2021
Congenital malformations of the nervous systemNAfinn-b-Q17_CONGEN_MALFO_NERVOUS_SYSTEM218,79216,380,466EuropeanMales and females2021
 Figure 2 

Details of GWAS in the present study (exposure).

Int J Med Sci Image

3.3. Causal effects of NO2 on neurosurgical multisystem diseases

As for NO2, we found that NO2 was positively associated with cerebral infarction and craniosynostosis, and negatively correlation with concussion in the European population, where the association between NO2 and cerebral infarction and concussion was more robust. NO2 was negatively associated with trigeminal neuralgia and transient ischemic attack in African American or Afro-Caribbean population. NO2 was positively correlation with stroke, and negatively correlation with spinal canal stenosis and spinal meningioma in the South Asian population, where the association between NO2 and spinal meningioma was more robust. As to East Asian population, NO2 was positively associated with trigeminal neuralgia (IVW: OR = 1.21, 95%CI: 1.02~1.43, P = 0.03), subarachnoid hemorrhage, pituitary adenoma and craniopharyngioma, focal brain injury, and negatively relevant to stroke and craniosynostosis, where the association between NO2 and subarachnoid hemorrhage was more robust. As to Greater Middle Eastern population, NO2 was positively associated with intracerebral hemorrhage, spinal canal stenosis, and negatively associated with malignant neoplasm of brain and other parts of CNS, where the relevance between NO2 and spinal canal stenosis was more robust. No causal correlation has been found between NO2 and other neurosurgical disorders in other populations (Fig.3, Fig.4 and Table S6-S10).

3.4. Causal effects of PM2.5 on neurosurgical multisystem diseases

As for PM2.5, we discovered that PM2.5 was positively correlation with cerebral infarction in the European population, where the association was robust. As for African American or Afro-Caribbean population, PM2.5 was negatively associated with epilepsy, subarachnoid hemorrhage, and diffuse brain injury, where the association between PM2.5 and subarachnoid hemorrhage was more robust. As for South Asian population, PM2.5 was positively associated with congenital malformations of the nervous system. As for East Asian population, PM2.5 was negatively associated with cervical spondylosis, where the association was robust. As for Greater Middle Eastern population, PM2.5 was positively correlation with concussion, and negatively correlation with congenital malformations of the nervous system. No causal correlation has been discovered between PM2.5 and other neurosurgical disorders in other populations (Fig.3, Fig.4 and Table S11-S15).

 Figure 3 

Causality of the risk for air pollution (NOx, NO2, PM2.5) in the world and Neurosurgical multisystem diseases outcomes (Positive result, p<0.05).

Int J Med Sci Image
 Figure 4 

Causality of the risk for air pollution (PM2.5-10, PM10, PM2.5absorbance) in the world and Neurosurgical multisystem diseases outcomes (Positive result, p<0.05).

Int J Med Sci Image

3.5. Causal effects of PM2.5-10 on neurosurgical multisystem diseases

As for PM2.5-10, we found that PM2.5-10 was positively correlation with subarachnoid hemorrhage, and negatively correlation with hydrocephalus in the European population. In African American or Afro-Caribbean population, PM2.5-10 was negatively associated with craniosynostosis and Congenital malformations of the nervous system. As for South Asian population, PM2.5-10 was negatively associated with stroke, and transient ischemic attack, where the association between PM2.5-10 and stroke was more robust. As for East Asian population, PM2.5-10 was negatively correlation with spinal osteochondrosis, where the correlation was robust. As to Greater Middle Eastern population, M2.5-10 was positively correlation with stroke and subarachnoid hemorrhage, and negatively correlation with focal brain injury. No causal correlation has been found between PM2.5-10 and other neurosurgical disorders in other populations (Fig.3, Fig.4 and Table S16-S20).

3.6. Causal effects of PM10 on neurosurgical multisystem diseases

As for PM10, we found that PM10 was negatively associated with spinal canal stenosis in the European population, where the association was robust. As for African American or Afro-Caribbean population, PM10 was positively relevant to Alzheimer's disease. As for East Asian population, PM10 was positively associated with cervical spondylosis, where the association was robust. As to Greater Middle Eastern, we found that PM10 was negatively associated with Parkinson's disease and Alzheimer's disease, where the association between PM10 and Parkinson's disease was more robust. In addition, PM10 was positively associated with spinal osteochondrosis and benign meningioma, where the association between PM10 and benign meningioma was more robust. No causal correlation has been found between PM10 and other neurosurgical disorders in other populations (Fig.3, Fig.4 and Table S21-S24).

3.7. Causal effects of PM2.5 absorbance on neurosurgical multisystem diseases

As for PM2.5 absorbance, we found that PM2.5 absorbance was positively correlation with epilepsy and negatively relevant to cervical spondylosis in the European population. As to African American or Afro-Caribbean population, PM2.5 absorbance was negatively associated with epilepsy, subarachnoid hemorrhage and diffuse brain injury, where the correlation between PM2.5 absorbance and subarachnoid hemorrhage was more robust. As for South Asian, PM2.5 absorbance was negatively relevant to benign meningioma, where the association was robust. Furthermore, PM2.5 absorbance was positively associated with hydrocephalus and diffuse brain injury. As for East Asian, we found that PM2.5 absorbance was negatively correlation with Alzheimer's disease and Pituitary adenoma and craniopharyngioma. No causal relevance has been found between PM2.5 absorbance and other neurosurgical disorders in other populations (Fig.3, Fig.4 and Table S25-S28).

3.8. Sensitivity analysis

Sensitivity analysis was used to weigh the dependability of the causal relevance between ambient air pollution and neurosurgical multisystem diseases. This analysis primarily comprised three components: heterogeneity, horizontal pleiotropy, and leave-one-out analysis. Heterogeneity was estimated via Cochran's Q test, P>0.05 manifesting no heterogeneity in the MR analysis. To guarantee the dependability of the conclusions, a random effects model was used for those with P<0.05. Additionally, the MR-Egger intercept was utilized to test for pleiotropy. P<0.05 represents pleiotropy, which showed results of the MR analysis are labile. The research indicates that instability occurs exclusively when there is a relevance between air pollution and neurosurgical diseases using the MR-Egger analysis method, whereas all other results remain robust (Table 2) (Table S29-S56). Overall, the sensitivity analysis conducted in this research corroborates the dependability of the given SNPs selected as genetic instruments, suggesting that air pollution constitutes a dangerous element for neurosurgical multisystem diseases.

4. Discussion

In recent years, ambient air pollution has emerged as an increasingly severe threat to human health, contributing to millions of premature deaths globally each year [39]. While numerous researches have extensively discovered the relevance between air pollution and the cardiovascular and respiratory systems [40, 41], there remains a paucity of systematic investigations into its causal association with neurosurgical multisystem diseases. Consequently, it is urgently imperative to search underlying risk elements and to develop effective preventive measures aimed at mitigating the disadvantageous health consequences of air pollution. Numerous prospective and observational researches have investigated the correlation between neurological diseases and air pollution across various racial groups. For instance, Ma et al. demonstrated that prolonged PM2.5 exposure is relevant to cognitive decline and an elevated dangerousness of Alzheimer's disease, attributed to amyloid accumulation in the brains of Chinese patients [5]. Conversely, Zhang et al. proceeded researches on the U.S. population and discovered no significant relevance between PM2.5 exposure and stroke. Furthermore, their findings indicated that stroke did not significantly alter or modulate the causal correlation between PM2.5 exposure and dementia [42]. In conclusion, the aforementioned studies did not systematically explore the correlation between air pollution and neurosurgical multisystem diseases, and their findings were devoid of genetic evidence. Consequently, this study tries to address this problem by exploring the potential genetic associations between six air pollution factors—namely PM2.5, PM2.5-10, PM10, PM2.5 absorbance, NO2 and NOx, and multiple neurological disorders.

 Table 2 

Sensitivity analyses of MR-Egger intercept regression and Cochrane Q tests (Positive result).

ExposuresPopulationOutcomes-Neurosurgical disordersOutcomes-DiseasesQ_MR.EggerQ_df_MR.EggerQ_pvalQ_IVWQ_df_IVWQ_pvalEgger_interceptsepval
NOxEuropeanfunctional diseasesmajor depressive disorder11.1140.0314.2650.01-0.16820.15820.3475
spinal and spinal cord diseasespinal meningioma4.8840.305.1250.400.20270.45850.6812
African American or Afro-Caribbeanfunctional diseasestrigeminal neuralgia6.38150.976.61160.980.01730.03610.6386
cerebrovascular diseasescerebral aneurysm16.70180.5420.65190.36-0.03310.01660.0624
South Asianother brain diseasesfocal brain injury17.23160.3718.73170.34-0.03660.03100.2544
East Asiancentral nervous system neoplasmsmalignant neoplasm of brain and other parts of cns3.6980.887.5090.580.17530.08960.0862
NO2Europeancerebrovascular diseasescerebral infarction1.6720.436.8430.08-0.00140.00060.1508
other brain diseasescraniosynostosis0.1620.920.7330.870.16990.22440.5279
other brain diseasesconcussion0.5920.740.7330.870.1750.04720.7466
African
American or
Afro-Caribbean
functional diseasestrigeminal neuralgia15.33250.9315.33260.950.00020.02710.9956
cerebrovascular diseasestransient ischemic attack20.36250.7320.79260.75-0.00570.00860.5155
South Asiancerebrovascular diseasesstroke12.10160.7412.41170.770.00410.00730.5857
spinal and spinal cord diseasespinal canal stenosis22.31210.3830.18220.110.03410.01250.0128
spinal and spinal cord diseasespinal meningioma10.36180.9210.38190.940.01840.11020.8693
East Asianfunctional diseasestrigeminal neuralgia5.6590.775.65100.840.00350.04150.9355
cerebrovascular diseasesstroke9.14100.529.24110.600.00220.00690.7603
cerebrovascular diseasessubarachnoid hemorrhage12.85120.3812.85130.460.00100.02140.9640
central nervous system neoplasmspituitary adenoma and craniopharyngioma12.0790.2112.47100.250.02730.05010.5986
other brain diseasescraniosynostosis12.0890.2113.42100.200.06730.06730.3437
other brain diseasesfocal brain injury8.5490.488.68100.560.01350.03620.7174
Greater Middle Easterncerebrovascular diseasesintracerebral hemorrhage14.91220.8720.38230.62-0.05150.02200.0289
spinal and spinal cord diseasespinal canal stenosis17.14220.7617.71230.77-0.00850.01120.4576
central nervous system neoplasmsmalignant neoplasm of brain and other parts of cns18.56180.4224.40190.180.19180.08060.0285
PM2.5Europeancerebrovascular diseasescerebral infarction2.9230.403.3840.500.00020.00040.5486
African
American or
Afro-Caribbean
functional diseasesepilepsy20.18220.5720.39230.62-0.00610.01340.6543
cerebrovascular diseasessubarachnoid hemorrhage28.53220.1628.62230.19-0.00610.02300.7916
other brain diseasesdiffuse brain injury19.83210.5323.20220.39-0.07590.04140.0805
South Asianother brain diseasescongenital malformations of the nervous system19.82240.7123.26250.56-0.09290.05010.0760
East Asianspinal and spinal cord diseasecervical spondylosis11.42110.4113.37120.340.00020.00010.1987
Greater Middle Easternother brain diseasesconcussion15.63260.9415.91270.95-0.00580.01100.6040
other brain diseasescongenital malformations of the nervous system20.45260.7720.46270.810.00620.06630.9265
PM2.5-10Europeancerebrovascular diseasessubarachnoid hemorrhage39.77390.4439.80400.480.00170.00940.8589
other brain diseaseshydrocephalus32.60360.6332.65370.67-0.00460.01990.8173
African American or Afro-Caribbeanother brain diseasescraniosynostosis7.91170.978.15180.98-0.04030.08120.6265
other brain diseasescongenital malformations of the nervous system13.89170.6713.93180.73-0.02030.10250.8451
South Asiancerebrovascular diseasesstroke8.2880.418.3090.500.00150.00980.8780
cerebrovascular diseasestransient ischemic attack3.77100.964.07110.970.01010.01830.5926
East Asianspinal and spinal cord diseasespinal osteochondrosis9.8370.209.8480.28-0.00850.08700.9247
Greater Middle Easterncerebrovascular diseasesstroke16.73210.7320.81220.530.01290.00640.0562
cerebrovascular diseasessubarachnoid hemorrhage20.84250.7021.92260.69-0.01670.01610.3093
other brain diseasesfocal brain injury34.69230.0635.40240.060.02130.03120.5008
PM10Europeancerebrovascular diseasesspinal canal stenosis16.29180.5716.63190.610.00800.01370.5650
African American or Afro-Caribbeanfunctional diseasesalzheimer's disease7.90120.7913.83130.39-0.02380.00980.0315
East Asianspinal and spinal cord diseasecervical spondylosis3.1880.924.3090.89-0.00020.000020.3194
Greater Middle Easternfunctional diseasesparkinson's disease14.17140.4414.22150.510.00430.01820.8176
functional diseasesalzheimer's disease17.73140.2219.47150.19-0.00710.00600.2615
spinal and spinal cord diseasespinal osteochondrosis12.04140.6017.48150.29-0.16680.07150.0351
central nervous system neoplasmsbenign meningioma9.05140.8311.50150.720.04530.02890.1396
PM2.5absorbanceEuropeanfunctional diseasesepilepsy5.9720.059.4330.02-0.06180.05740.3941
spinal and spinal cord diseasecervical spondylosis0.1820.910.1930.98-0.00040.00030.9173
African
American or
Afro-Caribbean
functional diseasesepilepsy20.00210.5220.28220.57-0.00710.01360.6078
cerebrovascular diseasessubarachnoid hemorrhage28.45210.1328.51220.16-0.00510.02380.8310
other brain diseasesdiffuse brain injury18.85200.5322.86210.35-0.08470.04230.0590
South Asiancentral nervous system neoplasmsbenign meningioma13.87130.3814.27140.430.02440.03990.5524
other brain diseaseshydrocephalus4.14130.995.25140.980.05010.04780.3130
other brain diseasesdiffuse brain injury8.61130.809.38140.810.04480.05100.3957
East Asianfunctional diseasesalzheimer's disease7.0690.637.52100.68-0.00560.00820.5161
central nervous system neoplasmspituitary adenoma and craniopharyngioma2.3590.982.37100.99-0.01060.06370.8720

This study is distinguished by several key aspects: 1. It presents the inaugural genetic evidence establishing a causal correlation between air pollution and neurosurgical multisystem disease; 2. It identifies specific variations in the impact of air pollution on neurological diseases across different racial and population groups; 3. It posits that a P-value of less than 0.05 in more than two distinct MR analyses indicates a robust correlation. The specific analysis results are as follows: 3.1. NO2 exposure is genetically predicted to significantly increase the risk of cerebral infarction in European populations, subarachnoid hemorrhage in East Asian populations, and Spinal canal stenosis in Greater Middle Eastern populations, while reducing the dangerousness of concussion in European populations and spinal meningioma in South Asian populations. 3.2. PM2.5 is a dangerousness element for cerebral infarction in European populations, and a protective factor for subarachnoid hemorrhage in African American or Afro-Caribbean populations and cervical spondylosis in East Asian populations. 3.3. PM2.5-10 exposure may be negatively related to stroke in South Asian populations and Spinal osteochondrosis in East Asian populations. 3.4. PM10 exposure may be positively associated with cervical spondylosis in East Asian populations and benign meningiomas in Greater Middle Eastern populations, but negatively associated with Spinal canal stenosis in European populations and Parkinson's disease in Greater Middle Eastern populations. 3.5. There may be a remarkable negative relevance between PM2.5 absorbance and subarachnoid hemorrhage in African American or Afro-Caribbean population and benign meningioma in South Asian population. 4. Air pollution is associated with the following diseases in more than two races and populations: 4.1. NO2: trigeminal neuralgia, stroke, spinal stenosis and craniosynostosis; 4.2. PM2.5: congenital malformations of the nervous system; 4.3. PM2.5-10: subarachnoid hemorrhage and stroke; 4.4. PM10: Alzheimer's Disease; 4.5. PM2.5 absorbance: epilepsy and diffuse brain injury. 5. From the perspective of different subspecialties of neurosurgery, the diseases associated with air pollution three or more times are as follows: 5.1. functional diseases: trigeminal neuralgia and epilepsy; 5.2. cerebrovascular diseases: stroke and subarachnoid hemorrhage; 5.3. spinal and spinal cord disease: spinal canal stenosis and cervical spondylosis; 5.4. other brain diseases: craniosynostosis, diffuse brain injury, focal brain injury and congenital malformations of the nervous system. 6. The following diseases were not found to be associated with air pollution: obsessive compulsive disorder, intracranial and intraspinal abscess, cervical spinal cord and nerve injuries, glioblastoma, malignant meningioma and benign neoplasm of brain and other parts of CNS.

Regarding functional diseases, this study identified a remarkable negative relevance between trigeminal neuralgia and exposure to NOx and NO2 within the African American or Afro-Caribbean population, while a positive association was observed with NO2 exposure in the East Asian population. Previous study on the correlation between trigeminal neuralgia and air pollution has not addressed the correlation with NOx and NO2, making this study the first to investigate this specific direction. Researchers in China identified no relevance between short-term air pollution exposure and epilepsy [43]. Conversely, a retrospective study conducted at a hospital indicated that air pollution, particularly elevated levels of PM2.5 and SO2, constitutes a risk factor for pediatric convulsions [44]. The current study elucidated that PM2.5 and PM2.5 absorbance are negatively relevant to African American or Afro-Caribbean populations from a genetic perspective. However, the mechanisms by which SNPs influence seizure susceptibility during pollutant exposure remain poorly understood, and there are notable racial disparities in the findings. For Parkinson's disease (PD), a retrospective study conducted by Korean researchers identified a strong relevance between NO2 exposure and the incidence and progression of Parkinson's disease (PD) [9]. In contrast, a study by Dutch researchers did not establish a remarkable relevance between air pollution exposure and the development of PD among local residents [45]. Our study indicates a remarkable relevance between PM10 exposure and the occurrence of PD in the Greater Middle Eastern population. These findings could inform the implementation of targeted public health interventions. Numerous researches have demonstrated that PM2.5 may elevate the incidence of Alzheimer's disease, potentially through mechanisms involving the reduction of DNA methylation levels, alterations in epigenetic regulation, damage to the CNS, and disruption of intestinal microecological balance [46]. The present study identifies a significant correlation between Alzheimer's disease and both PM10 and PM2.5 absorbance, thereby laying the groundwork for further investigation into the potential associations and underlying mechanisms linking this disease with air pollution.

Regarding cerebrovascular diseases, our study identified a remarkable relevance between NO2, PM2.5 and an elevated dangerousness of cerebral infarction in European populations. Notably, prior studies have not built a direct correlation between air pollution and cerebral infarction. Consequently, our findings offer novel insights into the etiology and progression of cerebral infarction, particularly within European cohorts. Additionally, existing literature suggests that air pollution exposure may heighten the dangerousness of ischemic stroke, especially among individuals with large artery and small vessel diseases. Short contact air pollution also enhances the risk of hemorrhagic stroke, but the effect of long-term exposure on hemorrhagic risk is unknown [12]. Our study identified that various air pollutants exert distinct effects across different ethnic groups. For example, elevated concentrations of NO2 were related to an increased dangerousness of stroke in South Asian populations, whereas the same pollutant appeared to have a protective effect in East Asian populations. The underlying mechanisms for these differential effects require further investigation. Hwang et al. demonstrated a significant relevance between air pollution and mortality due to subarachnoid hemorrhage, particularly among female patients. This heightened susceptibility in women may be attributed to their lower smoking rates compared to the general population, as well as anatomical and physiological differences such as smaller airway dimensions, increased airway reactivity, and greater deposition of particulate matter. [47]. Our research additionally identified a significant correlation between air pollution—specifically NO2, PM2.5, and PM2.5-10—and the incidence and progression of subarachnoid hemorrhage across nearly all ethnic groups.

Furthermore, we have, for the first time, elucidated a genetic basis for the causal relevance between air pollution and spinal cord diseases, including spinal stenosis and cervical spondylosis. This novel finding offers a foundational framework for future investigations into potential mechanisms and the formulation of preventive and control strategies.

Regarding central nervous system neoplasms, our consequences indicate a potential genetic relevance between air pollution and benign meningiomas. Specifically, we discovered a negative correlation between PM10 exposure and meningiomas in Greater Middle Eastern populations, and a positive relevance between PM2.5 exposure and meningiomas in South Asian populations. In contrast, Wu et al. conducted a cohort study on air pollution and benign brain tumors and found no remarkable relevance between air pollution and meningioma [48], This discrepancy may be attributed to factors such as racial differences and the limited sample size in their study, and our study was analyzed from a genetic perspective, which made it more credible and convincing. As for malignant brain tumors such as glioma, we have not yet found a genetic link between them and air pollution.

Regarding other neurological disorders, our study concentrated on the causal correlation between air pollution and craniosynostosis, as well as congenital malformations of the nervous system. Congenital malformations represent a significant reason of fetal death, infant mortality and morbidity [49]. Our consequences indicate a strong relevance between PM2.5, PM2.5-10 and congenital malformations of the central nervous system. This is in accordance with previous studies that have been thought have a strong association between PM10 exposure during the overall congenital malformations. Subsequent exposure to PM10 throughout pregnancy was associated with congenital heart disease, neurodevelopmental abnormalities, and tetralogy of Fallot. In contrast, PM2.5 and NO2 exposure was not relevant to congenital conditions or malformations [49]. Consequently, our study is the first to identify a relevance between PM2.5 and PM2.5-10 exposure and congenital malformations of the central nervous system, providing significant insights for disease prevention and control. As for craniosynostosis, we also reported it for the first time to provide ideas for follow-up work.

Air pollution has different impacts on the health of people in different regions, which may be caused by population stratification. Population stratification refers to the existence of subgroup structures (such as genetic background, socioeconomic status, race, etc.) in the study population, which leads to the distortion of exposure-disease associations [50]. In the study of air pollution, if the population in highly polluted areas also has other high-risk characteristics (such as poverty and poor medical conditions), it may wrongly attribute the health differences entirely to the pollution itself. Low-income areas are usually more polluted, but residents may also face higher stress, poorer diet and medical resources. These factors together exacerbate health risks [51]. Some genetic variations (such as GSTP1, TNF-α) may affect an individual's sensitivity to pollution. If the proportion of a specific ethnic group is high in a certain area, differences in "pollution resistance" may be observed [52].

Therefore, population stratification is an important source of deviation, but a comprehensive analysis needs to be conducted in combination with the characteristics of pollutants, climate and medical conditions. The future study design should give priority to controlling socioeconomic status, genetic background, or using instrumental variables (such as policy changes) to reduce confounding.

In this study, a comprehensive MR analysis was performed utilizing data from the GWAS database. The substantial sample size enhances the stability of the causal effect analysis and ensures consistency across various MR analytical methods. Additionally, the application of the MR-Egger analysis method augments the reliability and reproducibility of the investigation into the relevance between air pollution and multi-system diseases within the field of neurosurgery, while mitigating ethical concerns and research costs [53]. This study offers compelling genetic basis supporting the causal relevance between air pollution and neurosurgical multi-system diseases, thereby offering an innovative theoretical foundation for the prevention and cure of air pollution-induced neurological conditions. Notably, our study population encompasses data from ethnic groups across multiple regions, enhancing the comprehensiveness and rigor of our conclusions. Although the stabilized of our analysis, it is vital to realize the deficiencies of this study. Firstly, the exposure factors mainly selected in this study are PM2.5, PM2.5-10, PM10, PM2.5 absorbance, NO2 and NOx, so there is a lack of research on some specific air pollutants, such as O3, NO and SO2, so this study cannot provide more detailed analytical data to determine their impact on neurosurgical multisystem diseases. Furthermore, a fundamental assumption of MR analysis is the linear correlation between genetic variation, exposure factors, and outcomes. However, prior epidemiological studies indicate a nonlinear correlation between air pollution and disease [54]. Consequently, our study must rigorously account for potential nonlinear relationships or time-varying effects during the MR analysis. Despite certain drawbacks, our MR analysis yields valuable understandings into the genetic relevance between air pollution and neurosurgical multisystem disease. We believe that based on the consequences of this study, people will have a deeper insight of the underlying function of air pollution in neurological diseases in the future, so as to develop more effective prevention and control measures.

5. Recommendations for Future Investigations

Given the established causal correlation between ambient air pollution and neurosurgical multisystem diseases, several recommendations for future study are proposed. Firstly, it is imperative to elucidate the potential mechanisms through which air pollution interact with genetic elements, thereby increasing the dangerousness of neurosurgical multisystem diseases. This line of inquiry aims to identify and characterize the critical susceptibility windows for neurological diseases and to pinpoint underlying targets for intervention. Second, investigate the underlying interactions between air pollutants and genetic variants across different populations to determine whether specific genetic variants are more likely to be associated with particular neurological disorders. Third, as evidenced by this study, it is crucial to validate the causal correlation between air pollution and neurological diseases using data from multiple regions, ethnic groups, and datasets. Finally, large-scale prospective cohort studies will be essential to gather and monitor the long-term exposure of different populations to air pollution to build a more clearly causal correlation between exposure factors and outcomes in the future.

6. Conclusions

In conclusion, our study elucidates the environmental and societal ramifications of mitigating air pollution to diminish the dangerousness of multisystem diseases pertinent to neurosurgery. The implementation of robust air pollution prevention and cure way, the establishment of sustainable urban planning frameworks, the propelling of clean energy strategies, and the adoption of science-based occupational safeguards are pivotal in safeguarding public health. These consequences furnish critical evidence for policymakers, healthcare professionals, environmental organizations, and the general populace to advocate for and execute air quality enhancement initiatives on a global scale. Ultimately, it will benefit the whole world and improve human health.

Supplementary Material

Supplementary tables.

Attachment

Acknowledgements

We appreciate the work of the open GWAS project and UK Biobank for their invaluable efforts.

Funding

This work was supported by the Foundation of Science and Technology Department of Sichuan Province (Grant No. 2022YFS0322 and 2024YFFK0058).

Author contributions

Lirui Dai: Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Resources, Writing - original draft. Peizhi Zhou: Conceptualization, Supervision, Writing - review & editing. Shu Jiang: Conceptualization, Funding acquisition, Methodology, Writing - original draft.

Data availability

The original data are available in the open GWAS project (https://gwas.mrcieu.ac.uk/).

Competing Interests

The authors have declared that no competing interest exists.

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Author contact

Corresponding address Corresponding author: Peizhi Zhou, Department of Neurosurgery, West China Hospital of Sichuan University, Sichuan University, Chengdu, Sichuan, China. Email: peizhizhounsedu.cn.


Citation styles

APA
Dai, L., Jiang, S., Zhou, P. (2025). Causal Effects of Exposure to Air Pollution on the Risk of Neurosurgical Multi-system Diseases: A Worldwide Study of Mendelian Randomization. International Journal of Medical Sciences, 22(14), 3565-3580. https://doi.org/10.7150/ijms.115853.

ACS
Dai, L.; Jiang, S.; Zhou, P. Causal Effects of Exposure to Air Pollution on the Risk of Neurosurgical Multi-system Diseases: A Worldwide Study of Mendelian Randomization. Int. J. Med. Sci. 2025, 22 (14), 3565-3580. DOI: 10.7150/ijms.115853.

NLM
Dai L, Jiang S, Zhou P. Causal Effects of Exposure to Air Pollution on the Risk of Neurosurgical Multi-system Diseases: A Worldwide Study of Mendelian Randomization. Int J Med Sci 2025; 22(14):3565-3580. doi:10.7150/ijms.115853. https://www.medsci.org/v22p3565.htm

CSE
Dai L, Jiang S, Zhou P. 2025. Causal Effects of Exposure to Air Pollution on the Risk of Neurosurgical Multi-system Diseases: A Worldwide Study of Mendelian Randomization. Int J Med Sci. 22(14):3565-3580.

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