{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T13:24:38Z","timestamp":1776691478630,"version":"3.51.2"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T00:00:00Z","timestamp":1723593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>To evaluate the causal relationship between abdominal multi-organ iron content and PD risk using publicly available genome-wide association study (GWAS) data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We conducted MR analysis to assess the effects of iron content in various abdominal organs on PD risk, followed by reverse analysis. Additionally, MVMR analysis evaluated the independent effects of organ-specific iron content on PD. We utilized genetic variation data from the UK Biobank, including liver iron content (<jats:italic>n<\/jats:italic>\u2009=\u200932,858), spleen iron content (<jats:italic>n<\/jats:italic>\u2009=\u200935,324), and pancreas iron content (<jats:italic>n<\/jats:italic>\u2009=\u200925,617), as well as summary-level data for Parkinson\u2019s disease from the FinnGen (<jats:italic>n<\/jats:italic>\u2009=\u2009218,473) and two other large GWAS datasets of European populations (First dataset <jats:italic>n<\/jats:italic>\u2009=\u2009480,018; Second dataset <jats:italic>n<\/jats:italic>\u2009=\u20092,829). The primary MR analysis used the inverse variance-weighted (IVW) method, confirmed by MR-Egger and weighted median methods. Sensitivity analysis was performed to address potential pleiotropy and heterogeneity. Observational cohort results were validated through replication cohort analysis, followed by meta-analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>IVW analysis revealed a causal relationship between increased liver iron content and elevated risk of PD (OR\u2009=\u20091.27; 95% CI: 1.05\u20131.53; <jats:italic>p<\/jats:italic>\u2009=\u20090.015). No significant causal relationship was observed between spleen (OR\u2009=\u20091.00; 95% CI: 0.76\u20131.32; <jats:italic>p<\/jats:italic>\u2009=\u20090.983) and pancreatic (OR\u2009=\u20090.93; 95% CI: 0.72\u20131.20; <jats:italic>p<\/jats:italic>\u2009=\u20090.573) iron content and increased risk of PD. Meta-analysis of GWAS data for PD from three different sources using the random-effects IVW method showed a statistically significant causal relationship between liver iron content and the occurrence of PD (OR\u2009=\u20091.17, 95% CI: 1.01\u20131.35; <jats:italic>p<\/jats:italic>\u2009=\u20090.012).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study presents evidence from Mendelian randomization (MR) analysis indicating a significant causal link between increased liver iron content and a higher risk of Parkinson\u2019s disease (PD). These findings suggest that interventions targeting body iron metabolism, particularly liver iron levels, may be effective in preventing PD.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2024.1416014","type":"journal-article","created":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T04:57:45Z","timestamp":1723611465000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Abdominal multi-organ iron content and the risk of Parkinson\u2019s disease: a Mendelian randomization study"],"prefix":"10.3389","volume":"16","author":[{"given":"Mingrui","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fei","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chaotian","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guowei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong","family":"Kong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Peng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,8,14]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e557","DOI":"10.1212\/NXG.0000000000000557","article-title":"Genome-wide association study meta-analysis for Parkinson disease motor subtypes","volume":"7","author":"Alfradique-Dunham","year":"2021","journal-title":"Neurol. Genet."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1111\/bjh.14013","article-title":"HbH constant spring disease has lower serum ferritin relative to liver iron concentration (LIC): importance of LIC measurement and potential impact on serum ferritin thresholds for iron chelation","volume":"176","author":"Ang","year":"2017","journal-title":"Br. J. Haematol."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"4676","DOI":"10.3390\/ijms22094676","article-title":"The contribution of microglia to neuroinflammation in Parkinson's disease","volume":"22","author":"Badanjak","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1111\/jnc.13425","article-title":"Iron neurochemistry in Alzheimer's disease and Parkinson's disease: targets for therapeutics","volume":"139","author":"Belaidi","year":"2016","journal-title":"J. Neurochem."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1002\/mds.27730","article-title":"Ventral posterior substantia nigra iron increases over 3 years in Parkinson's disease","volume":"34","author":"Bergsland","year":"2019","journal-title":"Mov. Disord."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1093\/ije\/dyv071","article-title":"Mendelian randomization studies: a review of the approaches used and the quality of reporting","volume":"44","author":"Boef","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1093\/ije\/dyv080","article-title":"Mendelian randomization with invalid instruments: effect estimation and bias detection through egger regression","volume":"44","author":"Bowden","year":"2015","journal-title":"Int. J. Epidemiol."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1007\/s10654-015-0011-z","article-title":"Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors","volume":"30","author":"Burgess","year":"2015","journal-title":"Eur. J. Epidemiol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"260","DOI":"10.3324\/haematol.2019.232124","article-title":"Iron metabolism and iron disorders revisited in the hepcidin era","volume":"105","author":"Camaschella","year":"2020","journal-title":"Haematologica"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1016\/S1474-4422(18)30295-3","article-title":"Global, regional, and national burden of Parkinson's disease, 1990-2016: a systematic analysis for the global burden of disease study 2016","volume":"17","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1089\/ars.2021.0218","article-title":"Dysregulation of Iron homeostasis in the central nervous system and the role of Ferroptosis in neurodegenerative disorders","volume":"37","author":"David","year":"2022","journal-title":"Antioxid. Redox Signal."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"5396","DOI":"10.1038\/sj.emboj.7601409","article-title":"Ferroportin-mediated mobilization of ferritin iron precedes ferritin degradation by the proteasome","volume":"25","author":"De Domenico","year":"2006","journal-title":"EMBO J."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"4635","DOI":"10.1021\/acs.chemrev.2c00684","article-title":"Critical review on the mechanisms of Fe(2+) regeneration in the electro-Fenton process: fundamentals and boosting strategies","volume":"123","author":"Deng","year":"2023","journal-title":"Chem. Rev."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: an iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"126","DOI":"10.3390\/ph12030126","article-title":"Multilevel impacts of Iron in the brain: the cross talk between neurophysiological mechanisms, cognition, and social behavior","volume":"12","author":"Ferreira","year":"2019","journal-title":"Pharmaceuticals (Basel)"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1161\/CIRCULATIONAHA.118.035905","article-title":"Genetically determined levels of circulating cytokines and risk of stroke","volume":"139","author":"Georgakis","year":"2019","journal-title":"Circulation"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"2926","DOI":"10.1002\/sim.6522","article-title":"Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome","volume":"34","author":"Greco","year":"2015","journal-title":"Stat. Med."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1002\/jmri.25434","article-title":"Influence of regional iron on the motor impairments of Parkinson's disease: a quantitative susceptibility mapping study","volume":"45","author":"Guan","year":"2017","journal-title":"J. Magn. Reson. Imaging"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"1985","DOI":"10.1093\/ije\/dyx102","article-title":"Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption","volume":"46","author":"Hartwig","year":"2017","journal-title":"Int. J. Epidemiol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"802","DOI":"10.1016\/j.amjmed.2019.03.001","article-title":"Parkinson's disease and parkinsonism","volume":"132","author":"Hayes","year":"2019","journal-title":"Am. J. Med."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1002\/acm2.13096","article-title":"Reproducibility of liver iron concentration estimates in MRI through R2* measurement determined by least-squares curve fitting","volume":"21","author":"Headley","year":"2020","journal-title":"J. Appl. Clin. Med. Phys."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"e34408","DOI":"10.7554\/eLife.34408","article-title":"The MR-base platform supports systematic causal inference across the human phenome","volume":"7","author":"Hemani","year":"2018","journal-title":"eLife"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1007\/s12288-016-0735-2","article-title":"Evaluation of Iron overload in the heart and liver tissue by magnetic resonance imaging and its relation to serum ferritin and Hepcidin concentrations in patients with thalassemia syndromes","volume":"33","author":"Karakus","year":"2017","journal-title":"Indian J. Hematol. Blood Transfus."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1007\/s12185-008-0120-5","article-title":"Body iron metabolism and pathophysiology of iron overload","volume":"88","author":"Kohgo","year":"2008","journal-title":"Int. J. Hematol."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"7165387","DOI":"10.1155\/2022\/7165387","article-title":"Liquid-liquid phase separation promotes protein aggregation and its implications in Ferroptosis in Parkinson's disease dementia","volume":"2022","author":"Li","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/s00702-020-02149-3","article-title":"Parkinson's disease and iron","volume":"127","author":"Mochizuki","year":"2020","journal-title":"J. Neural Transm."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1126\/science.add7162","article-title":"Toward preventing Parkinson's disease","volume":"377","author":"Mollenhauer","year":"2022","journal-title":"Science"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"6493","DOI":"10.3390\/ijms22126493","article-title":"Hepcidin-Ferroportin interaction controls systemic Iron homeostasis","volume":"22","author":"Nemeth","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"3622","DOI":"10.1111\/bph.14567","article-title":"Treating Alzheimer's disease by targeting iron","volume":"176","author":"Nikseresht","year":"2019","journal-title":"Br. J. Pharmacol."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1002\/mds.26218","article-title":"High nigral iron deposition in LRRK2 and parkin mutation carriers using R2* relaxometry","volume":"30","author":"Pyatigorskaya","year":"2015","journal-title":"Mov. Disord."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1055\/s-0030-1255356","article-title":"Iron homeostasis, hepatocellular injury, and fibrogenesis in hemochromatosis: the role of inflammation in a noninflammatory liver disease","volume":"30","author":"Ramm","year":"2010","journal-title":"Semin. Liver Dis."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"a040501","DOI":"10.1101\/cshperspect.a040501","article-title":"Mendelian randomization: concepts and scope","volume":"12","author":"Richmond","year":"2022","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref9001","doi-asserted-by":"publisher","first-page":"1415","DOI":"10.1038\/s41588-021-00931-x","article-title":"A cross-population atlas of genetic associations for 220 human phenotypes","volume":"53","author":"Sakaue","year":"2021","journal-title":"Nat. Genet."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1093\/ije\/dyy262","article-title":"An examination of multivariable Mendelian randomization in the single-sample and two-sample summary data settings","volume":"48","author":"Sanderson","year":"2019","journal-title":"Int. J. Epidemiol."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"3253","DOI":"10.1681\/ASN.2016010098","article-title":"Mendelian randomization as an approach to assess causality using observational data","volume":"27","author":"Sekula","year":"2016","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1099","DOI":"10.1038\/s41593-019-0423-2","article-title":"Lewy pathology in Parkinson's disease consists of crowded organelles and lipid membranes","volume":"22","author":"Shahmoradian","year":"2019","journal-title":"Nat. Neurosci."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.metabol.2016.12.012","article-title":"Ectopic fat accumulation in the pancreas and its clinical relevance: a systematic review, meta-analysis, and meta-regression","volume":"69","author":"Singh","year":"2017","journal-title":"Metabolism"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.15252\/embr.201540558","article-title":"The Iron age of host-microbe interactions","volume":"16","author":"Soares","year":"2015","journal-title":"EMBO Rep."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"167992","DOI":"10.1016\/j.jmb.2023.167992","article-title":"Common mechanisms underlying alpha-synuclein-induced mitochondrial dysfunction in Parkinson's disease","volume":"435","author":"Sohrabi","year":"2023","journal-title":"J. Mol. Biol."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1959","DOI":"10.1007\/s00330-019-06450-y","article-title":"Impact of MRI technique on clinical decision-making in patients with liver iron overload: comparison of FerriScan- versus R2*-derived liver iron concentration","volume":"30","author":"Sussman","year":"2020","journal-title":"Eur. Radiol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1016\/j.nbd.2009.11.004","article-title":"Neuroinflammation in Parkinson's disease: its role in neuronal death and implications for therapeutic intervention","volume":"37","author":"Tansey","year":"2010","journal-title":"Neurobiol. Dis."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1136\/jnnp-2019-322042","article-title":"Brain iron deposition is linked with cognitive severity in Parkinson's disease","volume":"91","author":"Thomas","year":"2020","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41588-018-0099-7","article-title":"Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases","volume":"50","author":"Verbanck","year":"2018","journal-title":"Nat. Genet."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1097\/MOH.0000000000000236","article-title":"Hepcidin regulation in the anemia of inflammation","volume":"23","author":"Wang","year":"2016","journal-title":"Curr. Opin. Hematol."},{"key":"ref44","doi-asserted-by":"publisher","first-page":"36669","DOI":"10.1038\/srep36669","article-title":"Meta-analysis of brain iron levels of Parkinson's disease patients determined by postmortem and MRI measurements","volume":"6","author":"Wang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1045","DOI":"10.1016\/S1474-4422(14)70117-6","article-title":"The role of iron in brain ageing and neurodegenerative disorders","volume":"13","author":"Ward","year":"2014","journal-title":"Lancet Neurol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"761","DOI":"10.1016\/j.mri.2015.02.016","article-title":"Liver MRI is more precise than liver biopsy for assessing total body iron balance: a comparison of MRI relaxometry with simulated liver biopsy results","volume":"33","author":"Wood","year":"2015","journal-title":"Magn. Reson. Imaging"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1038\/s41531-022-00379-8","article-title":"Linking the phenotype of SNCA triplication with PET-MRI imaging pattern and alpha-synuclein CSF seeding","volume":"8","author":"Wurster","year":"2022","journal-title":"NPJ Parkinsons Dis."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"1255","DOI":"10.1007\/s00299-023-03024-7","article-title":"Research progress on the biosynthesis and delivery of iron-sulfur clusters in the plastid","volume":"42","author":"Yang","year":"2023","journal-title":"Plant Cell Rep."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1007\/s11064-021-03262-9","article-title":"Benefits of iron chelators in the treatment of Parkinson's disease","volume":"46","author":"Zeng","year":"2021","journal-title":"Neurochem. Res."}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2024.1416014\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T04:57:49Z","timestamp":1723611469000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2024.1416014\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,14]]},"references-count":50,"alternative-id":["10.3389\/fnagi.2024.1416014"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2024.1416014","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,14]]},"article-number":"1416014"}}