{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T04:48:59Z","timestamp":1793508539241,"version":"4.5.0"},"reference-count":41,"publisher":"American Medical Association (AMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>Genetic and environmental factors are linked to Parkinson disease (PD), but the role of genetic susceptibility in the association between traffic-related air pollution (TRAP) and PD remains unclear.<\/jats:p><\/jats:sec>Objective<\/jats:title>To assess the gene-environment interaction between the polygenic risk score (PRS) for PD and long-term TRAP exposure and to estimate the joint effect with PD risk.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>This population-based case-control study used a meta-analytical assessment of studies conducted in central California and Denmark. The Parkinson Environment and Genes (PEG) study in California (June 1, 2000, to July 31, 2017) included 634 patients with PD and 733 controls; the Parkinson Disease in Denmark (PASIDA) study (January 1, 2006, to December 31, 2017) included 966 patients with PD and 1045 controls. Data were analyzed from July 1 to October 31, 2024.<\/jats:p><\/jats:sec>Exposures<\/jats:title>PRS was computed by summing the effect estimates of well-known risk alleles from an existing genome-wide association study\u2019s summary statistics using participants\u2019 genetic arrays. TRAP exposure was estimated using dispersion models to calculate long-term exposure (10- or 15-year means with a 5-year lag) to traffic-related pollutants (represented by carbon monoxide [CO] levels) at participants\u2019 residences.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>The main outcome was diagnosis of PD. Using multivariable logistic regression, PD risk was estimated from interactions between PRS (per SD) and TRAP exposure (per IQR), with joint effects based on low (quartiles 1-3) and high (quartile 4) exposure levels.<\/jats:p><\/jats:sec>Results<\/jats:title>A total of 1600 patients with PD (mean [SD] age, 65.1 [9.9] years; 990 [61.9%] male) and 1778 controls (mean [SD] age, 64.5 [10.3] years; 992 [55.8%] male) were included. Meta-analytical estimates suggest that both higher PRS and increased TRAP exposure increased PD risk, with an interaction effect estimate of 1.06 (95% CI, 1.00-1.12). Joint effect analysis indicated that individuals with both high PRS and high TRAP exposure were at greatest risk of PD (odds ratio, 3.05; 95% CI, 2.23-4.19) compared with the reference group with a low PRS and low TRAP exposure, suggesting a synergistic effect.<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>In this gene-environment interaction study, a combination of long-term air pollution exposure and genetic susceptibility strongly contributed to the risk of developing PD. Widespread exposure to air pollution makes TRAP an important modifiable risk factor affecting large populations globally, particularly individuals with genetic vulnerability.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.0854","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T15:32:02Z","timestamp":1742225522000},"page":"e250854","source":"Crossref","is-referenced-by-count":16,"title":["Interaction Between Traffic-Related Air Pollution and Parkinson Disease Polygenic Risk Score"],"prefix":"10.1001","volume":"8","author":[{"given":"Dayoon","family":"Kwon","sequence":"first","affiliation":[{"name":"Department of Epidemiology, Fielding School of Public Health, UCLA (University of California, Los Angeles), Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly C.","family":"Paul","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Kusters","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Fielding School of Public Health, UCLA (University of California, Los Angeles), Los Angeles"},{"name":"Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles"},{"name":"Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, UCLA, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, School of Population and Public Health, University of California, Irvine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeff M.","family":"Bronstein","sequence":"additional","affiliation":[{"name":"Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina M.","family":"Lill","sequence":"additional","affiliation":[{"name":"Institute of Epidemiology and Social Medicine, University of M\u00fcnster, M\u00fcnster, Germany."},{"name":"Ageing Epidemiology Research Unit, School of Public Health, Imperial College, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Ketzel","sequence":"additional","affiliation":[{"name":"Department of Environmental Science, Aarhus University, Roskilde, Denmark"},{"name":"Global Centre for Clean Air Research, Department of Civil and Environmental Engineering, University of Surrey, Guildford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ole","family":"Raachou-Nielsen","sequence":"additional","affiliation":[{"name":"Department of Environmental Science, Aarhus University, Roskilde, Denmark"},{"name":"Danish Cancer Institute, Danish Cancer Society, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnni","family":"Hansen","sequence":"additional","affiliation":[{"name":"Danish Cancer Institute, Danish Cancer Society, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Ritz","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Fielding School of Public Health, UCLA (University of California, Los Angeles), Los Angeles"},{"name":"Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","published-online":{"date-parts":[[2025,3,17]]},"reference":[{"issue":"5","key":"zoi250065r1","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/S1474-4422(18)30499-X","article-title":"Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.","volume":"18","author":"GBD 2016 Neurology Collaborators","year":"2019","journal-title":"Lancet Neurol"},{"issue":"10291","key":"zoi250065r2","doi-asserted-by":"publisher","first-page":"2284","DOI":"10.1016\/S0140-6736(21)00218-X","article-title":"Parkinson\u2019s disease.","volume":"397","author":"Bloem","year":"2021","journal-title":"Lancet"},{"issue":"10","key":"zoi250065r3","doi-asserted-by":"publisher","first-page":"e551","DOI":"10.1016\/S2468-2667(20)30190-0","article-title":"The burden of neurological diseases in Europe: an analysis for the Global Burden of Disease Study 2017.","volume":"5","author":"Deuschl","year":"2020","journal-title":"Lancet Public Health"},{"issue":"12","key":"zoi250065r4","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1016\/S1474-4422(19)30320-5","article-title":"Identification of novel risk loci, causal insights, and heritable risk for Parkinson\u2019s disease: a meta-analysis of genome-wide association studies.","volume":"18","author":"Nalls","year":"2019","journal-title":"Lancet Neurol"},{"issue":"5","key":"zoi250065r5","doi-asserted-by":"publisher","first-page":"894","DOI":"10.1002\/mds.28922","article-title":"Air pollution and the risk of Parkinson\u2019s disease: a review.","volume":"37","author":"Murata","year":"2022","journal-title":"Mov Disord"},{"key":"zoi250065r6","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2022.107667","article-title":"Long-term air pollution exposure and Parkinson\u2019s disease mortality in a large pooled European cohort: an ELAPSE study.","volume":"171","author":"Cole-Hunter","year":"2023","journal-title":"Environ Int"},{"issue":"6","key":"zoi250065r7","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1001\/archneurol.2010.101","article-title":"Interaction between ABCB1 and professional exposure to organochlorine insecticides in Parkinson disease.","volume":"67","author":"Dutheil","year":"2010","journal-title":"Arch Neurol"},{"key":"zoi250065r8","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1016\/j.envres.2016.09.006","article-title":"Gene-environment interactions linking air pollution and inflammation in Parkinson\u2019s disease.","volume":"151","author":"Lee","year":"2016","journal-title":"Environ Res"},{"issue":"6","key":"zoi250065r9","doi-asserted-by":"publisher","first-page":"964","DOI":"10.1289\/ehp.0800277","article-title":"Dopamine transporter genetic variants and pesticides in Parkinson\u2019s disease.","volume":"117","author":"Ritz","year":"2009","journal-title":"Environ Health Perspect"},{"issue":"5","key":"zoi250065r10","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1289\/ehp.1408976","article-title":"Organophosphate pesticide exposures, nitric oxide synthase gene variants, and gene-pesticide interactions in a case-control study of Parkinson\u2019s disease, California (USA).","volume":"124","author":"Paul","year":"2016","journal-title":"Environ Health Perspect"},{"issue":"7","key":"zoi250065r11","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1093\/aje\/kwx227","article-title":"Current challenges and new opportunities for gene-environment interaction studies of complex diseases.","volume":"186","author":"McAllister","year":"2017","journal-title":"Am J Epidemiol"},{"issue":"10","key":"zoi250065r12","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1136\/jnnp-2020-323646","article-title":"Parkinson\u2019s disease determinants, prediction and gene-environment interactions in the UK Biobank.","volume":"91","author":"Jacobs","year":"2020","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"1","key":"zoi250065r13","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1186\/s12883-017-0978-z","article-title":"Parkinson disease polygenic risk score is associated with Parkinson disease status and age at onset but not with alpha-synuclein cerebrospinal fluid levels.","volume":"17","author":"Ibanez","year":"2017","journal-title":"BMC Neurol"},{"issue":"3","key":"zoi250065r14","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1001\/jamaneurol.2017.4206","article-title":"Association of polygenic risk score with cognitive decline and motor progression in Parkinson disease.","volume":"75","author":"Paul","year":"2018","journal-title":"JAMA Neurol"},{"issue":"4","key":"zoi250065r15","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1002\/mds.26505","article-title":"A cumulative genetic risk score predicts progression in Parkinson\u2019s disease.","volume":"31","author":"Pihlstr\u00f8m","year":"2016","journal-title":"Mov Disord"},{"issue":"pt 1","key":"zoi250065r16","doi-asserted-by":"publisher","DOI":"10.1016\/j.envres.2023.117434","article-title":"Traffic-related air pollution and Parkinson\u2019s disease in central California.","volume":"240","author":"Kwon","year":"2024","journal-title":"Environ Res"},{"issue":"3","key":"zoi250065r17","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1289\/ehp.1409313","article-title":"Traffic-related air pollution and Parkinson\u2019s disease in Denmark: a case-control study.","volume":"124","author":"Ritz","year":"2016","journal-title":"Environ Health Perspect"},{"key":"zoi250065r18","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/j.parkreldis.2019.01.018","article-title":"Clinical progression in Parkinson\u2019s disease with features of REM sleep behavior disorder: a population-based longitudinal study.","volume":"62","author":"Duarte Folle","year":"2019","journal-title":"Parkinsonism Relat Disord"},{"issue":"1","key":"zoi250065r19","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1001\/archneur.56.1.33","article-title":"Diagnostic criteria for Parkinson disease.","volume":"56","author":"Gelb","year":"1999","journal-title":"Arch Neurol"},{"issue":"3","key":"zoi250065r20","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1136\/jnnp.55.3.181","article-title":"Accuracy of clinical diagnosis of idiopathic Parkinson\u2019s disease: a clinico-pathological study of 100 cases.","volume":"55","author":"Hughes","year":"1992","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"3","key":"zoi250065r21","first-page":"A4391","article-title":"Validation of hospital register-based diagnosis of Parkinson\u2019s disease.","volume":"59","author":"Wermuth","year":"2012","journal-title":"Dan Med J"},{"issue":"188","key":"zoi250065r23","first-page":"1","article-title":"Adverse reproductive health outcomes and exposure to gaseous and particulate-matter air pollution in pregnant women.","volume":"2016","author":"Wu","year":"2016","journal-title":"Res Rep Health Eff Inst"},{"issue":"1","key":"zoi250065r24","doi-asserted-by":"publisher","DOI":"10.2202\/1934-2659.1510","article-title":"Modeling traffic-emitted ultrafine particle concentration and intake fraction in Corpus Christi, Texas.","volume":"6","author":"Yuan","year":"2011","journal-title":"Chem Prod Process Model"},{"issue":"4","key":"zoi250065r25","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1080\/10962247.2018.1548387","article-title":"Trends in passenger exposure to carbon monoxide inside a vehicle on an arterial highway of the San Francisco Peninsula over 30 years: a longitudinal study.","volume":"69","author":"Flachsbart","year":"2019","journal-title":"J Air Waste Manag Assoc"},{"issue":"1","key":"zoi250065r26","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.envint.2005.05.020","article-title":"A review of traffic-related air pollution exposure assessment studies in the developing world.","volume":"32","author":"Han","year":"2006","journal-title":"Environ Int"},{"issue":"1-4","key":"zoi250065r28","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1504\/IJEP.2011.047337","article-title":"Evaluation of AirGIS: a GIS-based air pollution and human exposure modelling system.","volume":"47","author":"Ketzel","year":"2011","journal-title":"Int J Environ Pollut"},{"key":"zoi250065r29","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.atmosenv.2018.10.036","article-title":"Development and performance evaluation of new AirGIS\u2014a GIS based air pollution and human exposure modelling system.","volume":"198","author":"Khan","year":"2019","journal-title":"Atmos Environ"},{"issue":"10","key":"zoi250065r30","doi-asserted-by":"publisher","first-page":"2264","DOI":"10.1002\/mds.28760","article-title":"Increased menopausal age reduces the risk of Parkinson\u2019s disease: a mendelian randomization approach.","volume":"36","author":"Kusters","year":"2021","journal-title":"Mov Disord"},{"issue":"3","key":"zoi250065r31","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcae146","article-title":"Genome-wide meta-analysis of short-tandem repeats for Parkinson\u2019s disease risk using genotype imputation.","volume":"6","author":"Ohlei","year":"2024","journal-title":"Brain Commun"},{"issue":"13","key":"zoi250065r32","doi-asserted-by":"publisher","first-page":"1618","DOI":"10.1096\/fj.04-1945fje","article-title":"Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase.","volume":"18","author":"Block","year":"2004","journal-title":"FASEB J"},{"issue":"5","key":"zoi250065r33","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1111\/jnc.12231","article-title":"The role of MAC1 in diesel exhaust particle-induced microglial activation and loss of dopaminergic neuron function.","volume":"125","author":"Levesque","year":"2013","journal-title":"J Neurochem"},{"key":"zoi250065r34","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1186\/1742-2094-8-105","article-title":"Air pollution & the brain: subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease.","volume":"8","author":"Levesque","year":"2011","journal-title":"J Neuroinflammation"},{"issue":"8","key":"zoi250065r35","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1289\/ehp.1002986","article-title":"Diesel exhaust activates and primes microglia: air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity.","volume":"119","author":"Levesque","year":"2011","journal-title":"Environ Health Perspect"},{"issue":"1","key":"zoi250065r36","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/0272-0590(86)90199-5","article-title":"Disposition and metabolism of [14C]dibenzo[c,g]carbazole aerosols in rats after inhalation.","volume":"7","author":"Bond","year":"1986","journal-title":"Fundam Appl Toxicol"},{"issue":"1","key":"zoi250065r37","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1093\/toxsci\/kfaa055","article-title":"Diesel exhaust extract exposure induces neuronal toxicity by disrupting autophagy.","volume":"176","author":"Barnhill","year":"2020","journal-title":"Toxicol Sci"},{"issue":"3","key":"zoi250065r38","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1007\/s10565-021-09618-9","article-title":"Diesel exhaust exposure alters the expression of networks implicated in neurodegeneration in zebrafish brains.","volume":"39","author":"Jami","year":"2023","journal-title":"Cell Biol Toxicol"},{"issue":"1","key":"zoi250065r39","doi-asserted-by":"publisher","first-page":"13","DOI":"10.2131\/jts.38.13","article-title":"Exposure to diesel exhaust during fetal period affects behavior and neurotransmitters in male offspring mice.","volume":"38","author":"Yokota","year":"2013","journal-title":"J Toxicol Sci"},{"issue":"2","key":"zoi250065r40","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1177\/0192623307313011","article-title":"Long-term air pollution exposure is associated with neuroinflammation, an altered innate immune response, disruption of the blood-brain barrier, ultrafine particulate deposition, and accumulation of amyloid beta-42 and alpha-synuclein in children and young adults.","volume":"36","author":"Calder\u00f3n-Garcidue\u00f1as","year":"2008","journal-title":"Toxicol Pathol"},{"issue":"1","key":"zoi250065r41","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1038\/s41531-024-00633-1","article-title":"Genetic susceptibility modifies the association of long-term air pollution exposure on Parkinson\u2019s disease.","volume":"10","author":"Huang","year":"2024","journal-title":"NPJ Parkinson Dis"},{"key":"zoi250065r22","unstructured":"Benson? PE, Pinkerman? KO. CALINE4, a dispersion model for predicting air pollutant concentrations near roadways. Report No. FHWA\/CA\/TL-84\/15. Office of Transportation Laboratory, California Department of Transportation. 1984. Accessed August 29, 2023. https:\/\/www.weblakes.com\/products\/calroads\/resources\/docs\/CALINE4.pdf"},{"key":"zoi250065r27","unstructured":"AirGIS. Aarhus University Department of Environmental Science. Accessed February 10, 2025. https:\/\/envs.au.dk\/en\/research-areas\/air-pollution-emissions-and-effects\/the-monitoring-program\/air-pollution-models\/airgis"}],"container-title":["JAMA Network Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/articlepdf\/2831648\/kwon_2025_oi_250065_1741626325.90895.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T15:32:05Z","timestamp":1742225525000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamanetworkopen\/fullarticle\/2831648"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,17]]},"references-count":41,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3,3]]}},"URL":"https:\/\/doi.org\/10.1001\/jamanetworkopen.2025.0854","relation":{},"ISSN":["2574-3805"],"issn-type":[{"value":"2574-3805","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,17]]}}}