Kang, XiaoyingPloner, AlexanderPedersen, Nancy LBandres-Ciga, SaraNoyce, Alastair JWirdefeldt, KarinWilliams, Dylan M2023-02-092023-02-092020-12-11Kang X, Ploner A, Pedersen NL, Bandres-Ciga S, Noyce AJ, Wirdefeldt K, et al. Tumor Necrosis Factor Inhibition and Parkinson Disease: A Mendelian Randomization Study. Neurology. 2021 Mar 23;96(12):e1672-e1679.http://hdl.handle.net/10668/17200To evaluate the effects of long-term tumor necrosis factor (TNF) inhibition on the risk and age at onset of Parkinson disease (PD), we performed a 2-sample Mendelian randomization study using genome-wide association studies (GWAS) summary statistics. Genetic variants in the vicinity of TNFRSF1A, the gene encoding TNF receptor 1 (TNFR1), were identified as predictive of pharmacologic blockade of TNFR1 signaling by anti-TNF therapy, based on genetic associations with lower circulating C-reactive protein (CRP; GWAS n = 204,402). The effects of TNF-TNFR1 inhibition were estimated for PD risk (ncases/controls = 37,688/981,372) and age at PD onset (n = 28,568) using GWAS data from the International Parkinson's Disease Genomics Consortium and 23andMe, Inc. To validate variants as proxies of long-term anti-TNF treatment, we also assessed whether variant associations reflected anticipated effects of TNFR1 inhibition on Crohn disease, ulcerative colitis, and multiple sclerosis risk (n = 38,589-45,975). TNF-TNFR1 signaling inhibition was not estimated to affect PD risk (odds ratio [OR] per 10% lower circulating CRP = 0.99; 95% confidence interval [CI] 0.91-1.08) or age at onset (0.13 years later onset; 95% CI -0.66 to 0.92). In contrast, genetically indexed TNF-TNFR1 signaling blockade predicted reduced risk of Crohn disease (OR 0.75; 95% CI 0.65-0.86) and ulcerative colitis (OR 0.84; 95% CI 0.74-0.97) and increased multiple sclerosis risk (OR 1.57; 95% CI 1.36-1.81). Findings were consistent across models using different genetic instruments and Mendelian randomization estimators. Our findings do not imply that TNF-TNFR1 signaling inhibition will prevent or delay PD onset. This study provides Class II evidence that TNF-TNFR1 signaling inhibition is not associated with the risk or age at onset of PD.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/Age of OnsetAgedC-Reactive ProteinFemaleGenome-Wide Association StudyHumansInflammatory Bowel DiseasesMaleMendelian Randomization AnalysisMiddle AgedParkinson DiseasePolymorphism, Single NucleotideReceptors, Tumor Necrosis Factor, Type IRisk FactorsTumor Necrosis Factor InhibitorsTumor Necrosis Factor-alpharesearch article33608417open accessMendelianaEnfermedad de ParkinsonEnfermedades inflamatorias del intestinoEstudio de asociación del genoma completoFactor de necrosis tumoral alfa10.1212/WNL.00000000000116301526-632XPMC8032365https://n.neurology.org/content/neurology/96/12/e1672.full.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032365/pdf