Objective To investigate the potential causal relationships between major ambient air pollutants and common neurodevelopmental disorders (NDDs), so as to explore the role of environmental exposure in the pathogenesis of NDDs from a genetic perspective. Methods A two-sample Mendelian randomization(MR) design was adopted, drawing on large-scale genome-wide association study (GWAS) summary data from individuals of European ancestry.Five common air pollutants (PM2.5,PM2.5-10, PM10, NO2, NOX) served as exposures and three major NDDs including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD) and Tourette syndrome (TS) were considered as outcomes.The inverse-variance weighted (IVW) method was employed as the primary analytical approach, complemented by weighted median, MR-Egger regression, simple mode, and weighted mode estimators to ensure robustness.Sensitivity analysis included heterogeneity testing (Cochran's Q), horizontal pleiotropy assessment (MR-Egger intercept), MR-PRESSO analysis (global test, outlier detection, and distortion test), and leave-one-out analysis to evaluate the stability and reliability of the causal estimates. Results The MR analysis showed that exposure to PM2.5 (OR=2.63, 95%CI: 1.73 - 4.01, P<0.01), NO2(OR=1.56, 95%CI:1.13 - 2.16, P<0.01) and NOx(OR=1.69, 95%CI: 1.23 - 2.34, P<0.01) was significantly associated with an increased risk of ADHD, and these associations remained consistent across multiple complementary analytical methods.No significant causal effects were observed for PM2.5-10 or PM10 on ADHD, nor for any air pollutants on ASD or TS (P>0.05).Sensitivity analysis indicated no evidence of directional pleiotropy based on the MR-Egger intercepts,and the robustness of the causl estimate was further supported by leave-one-out analysis.While some heterogeneity and potential outlier SNPs were detected, MR-PRESSO distortion tests showed no significant bias in causal estimates (P>0.05), reinforcing the robustness of the original findings. Conclusion Air pollutants PM2.5,NO2 and NOX are confirmed as environmental risk factors contributing to the development of ADHD, indicating the critical public health importance of enhancing air pollution control measures for the prevention and intervention of NDDs.
Key words
air pollution /
neurodevelopmental disorders /
genome-wide association study /
Mendelian randomization
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References
[1] American Psychiatric Association.Diagnostic and statistical manual of mental disorders: DSM-5[M].5th ed.Washington DC:American Psychiatric Pub,2013:50-59.
[2] Sigurdardottir KR, Hannesdottir DK, Hauksdottir B, et al.Incidence, co-occurring psychiatric conditions, and sex differences in young people without intellectual impairment who are autistic, ADHD, or autistic-ADHD: A population-based cross-sectional study in Iceland[J].Lancet Child Adolesc Health, 2025,9(7):459-469.
[3] Ayano G, Demelash S, Gizachew Y, et al.The global prevalence of attention deficit hyperactivity disorder in children and adolescents: An umbrella review of Meta-analyses[J].J Affect Disord, 2023,339:860-866.
[4] Johnson KA, Worbe Y, Foote KD, et al.Tourette syndrome:Clinical features, pathophysiology, and treatment[J].Lancet Neurol, 2023, 22(2): 147-158.
[5] Gidziela A, Ahmadzadeh YI, Michelini G, et al.A Meta-analysis of genetic effects associated with neurodevelopmental disorders and co-occurring conditions[J].Nat Hum Behav, 2023, 7(4): 642-656.
[6] Marshall M.The hidden links between mental disorders[J].Nature, 2020, 581(7806): 19-21.
[7] 姜妍妍, 童娟, 陶芳标.生命早期空气污染物暴露与儿童神经发育障碍的研究进展[J].环境与职业医学, 2024, 41(7): 828-833.
Jiang YY, Tong J, Tao FB.Research progress on early-life exposure to air pollutants and neurodevelopmental disorders in children[J].Environ Occup Med, 2024, 41(7): 828-833.(in Chinese)
[8] O'Sharkey K, Mitra S, Chow T, et al.Air pollution and autism spectrum disorder: Unveiling multipollutant risks and sociodemographic influences in California[J].Environ Health Perspect,2025,133(6):67010.
[9] Murphy MS, Abdulaziz KE, Lavigne É, et al.Association between prenatal air pollutant exposure and autism spectrum disorders in young children: A matched case-control study in Canada[J].Environ Res, 2024, 261: 119706.
[10] Compa M, Baumbach C, Kaczmarek-Majer K, et al.Air pollution and attention in Polish schoolchildren with and without ADHD[J].Sci Total Environ, 2023, 892: 164759.
[11] Chang YT, Jung CR, Chang YC, et al.Prenatal and postnatal exposure to PM2.5 and the risk of tic disorders[J].Paediatr Perinat Epidemiol, 2023, 37(3): 191-200.
[12] Skrivankova VW, Richmond RC, Woolf BAR, et al.Strengthening the reporting of observational studies in epidemiology using mendelian randomization: The STROBE-MR statement[J].JAMA, 2021, 326(16): 1614-1621.
[13] Wootton RE, Jones HJ, Sallis HM.Mendelian randomisation for psychiatry: How does it work, and what can it tell us?[J].Mol Psychiatry, 2022, 27(1): 53-57.
[14] Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium.Meta-analysis of GWAS of over 16 000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia[J].Mol Autism, 2017, 8: 21.
[15] Demontis D, Walters GB, Athanasiadis G, et al.Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains[J].Nat Genet, 2023, 55(2): 198-208.
[16] Yu D, Sul JH, Tsetsos F, et al.Interrogating the Genetic determinants of Tourette's syndrome and other Tic disorders through genome-wide association studies[J].Am J Psychiatry, 2019, 176(3): 217-227.
[17] Garfield V, Salzmann A, Burgess S, et al.A guide for selection of genetic instruments in mendelian randomization studies of type 2 diabetes and HbA1c:Toward an integrated approach[J].Diabetes,2023,72(2):175-183.
[18] Burgess S, Foley CN, Allara E, et al.A robust and efficient method for Mendelian randomization with hundreds of genetic variants[J].Nat Commun,2020,11(1):376.
[19] Lin Z, Deng Y, Pan W.Combining the strengths of inverse-variance weighting and Egger regression in Mendelian randomization using a mixture of regressions model[J].PLoS Genet,2021,17(11):e1009922.
[20] Chen WJ, Rector-Houze AM, Guxens M, et al.Susceptible windows of prenatal and postnatal fine particulate matter exposures and attention-deficit hyperactivity disorder symptoms in early childhood[J].Sci Total Environ, 2024, 912: 168806.
[21] Zhao J, He T, Wang F, et al.Association of prenatal and postnatal exposure to air pollution with clinically diagnosed attention deficit hyperactivity disorder: A systematic review[J].Front Public Health, 2024, 12: 1396251.
[22] Chen YC, Gui ZH, Bao WW, et al.Chronic exposure to indoor air pollutants in association with attention-deficit/hyperactivity disorder symptoms in Chinese schoolchildren: A cross-sectional study[J].Neurotoxicology, 2023, 94: 182-190.
[23] Zeng HX, Meng WJ, Zeng QG, et al.Long-term effects of PM(2.5) constituents on childhood attention deficit hyperactivity disorder: Evidence from a large population-based study in the Pearl River Delta Region, China[J].Environ Res, 2025, 277: 121641.
[24] Chauhan R, Dande S, Hood DB, et al.Particulate matter 2.5 (PM2.5)-associated cognitive impairment and morbidity in humans and animal models: A systematic review[J].J Toxicol Environ Health B Crit Rev,2025,28(4):233-263.
[25] Liu F, Liu C, Liu Y, et al.Neurotoxicity of the air-borne particles: From molecular events to human diseases[J].J Hazard Mater, 2023, 457: 131827.
[26] Thygesen M, Holst GJ, Hansen B, et al.Exposure to air pollution in early childhood and the association with attention-deficit/hyperactivity disorder[J].Environ Res, 2020, 183: 108930.
[27] Min JY, Min KB.Exposure to ambient PM10 and NO2 and the incidence of attention-deficit hyperactivity disorder in childhood[J].Environ Int, 2017, 99: 221-227.
[28] Dang J, Wang Y, Ma N, et al.The impact of long-term exposure to NO2, O3, and their oxidative potential on adolescents' mental health, and the protective role of school-based greenness[J].Environ Int,2025,195:109212.
[29] Lane M, Oyster E, Luo Y, et al.The effects of air pollution on neurological diseases: A narrative review on causes and mechanisms[J].Toxics, 2025, 13(3): 207.
[30] Gong T, Almqvist C, Bölte S, et al.Exposure to air pollution from traffic and neurodevelopmental disorders in Swe-dish twins[J].Twin Res Hum Genet, 2014, 17(6): 553-562.
[31] Pagalan L, Bickford C, Weikum W, et al.Association of prenatal exposure to air pollution with autism spectrum disorder[J].JAMA Pediatr, 2019, 173(1): 86-92.
[32] Hirota T, King BH.Autism spectrum disorder: A review [J].JAMA, 2023, 329(2): 157-168.
[33] Ha S.Air pollution and neurological development in children[J].Dev Med Child Neurol, 2021, 63(4): 374-381.
[34] Morrel J, Dong M, Rosario MA, et al.A systematic review of air pollution exposure and brain structure and function during development[J].Environ Res, 2025, 275: 121368.
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