Tumor necrosis factor (TNF) inhibition is under investigation as a therapeutic strategy for Parkinson's disease (PD) and REM sleep behavior disorder (RBD), yet supporting genetic evidence is limited. We used Summary-data-based Mendelian Randomization (SMR) to test whether expression level of ten TNF-related genes were causally linked to PD risk, PD progression, or RBD risk. We also analyzed associations between common and rare variants in these genes, and performed pathway specific polygenic risk score analysis, with PD. Overall, our findings do not support a genetic link between the TNF signaling and PD or RBD, arguing against this pathway as a genetically validated therapeutic target.

Z.G-O. received consultancy fees from Lysosomal Therapeutics Inc. (LTI), Idorsia, Prevail Therapeutics, Ono Therapeutics, Denali, Handl Therapeutics, Neuron23, Bial Biotech, Bial, UCB, Capsida, Vanqua bio, Congruence Therapeutics, Takeda, Jazz Guidepoint, Lighthouse and Deerfield. The remaining authors declare no competing interests. A.J.N. reports grants from Parkinson's UK, Barts Charity, Cure Parkinson's, National Institute for Health and Care Research, Innovate UK, the Medical College of Saint Bartholomew's Hospital Trust, Alchemab, Aligning Science Across Parkinson's Global Parkinson's Genetics Program (ASAP-GP2) and the Michael J Fox Foundation. A.J.N. reports fees from AstraZeneca, AbbVie, Bial, and Britannia. K.S. reports grant from Parkinson Canada, Aligning Science Across Parkinson's Global Parkinson's Genetics Program (ASAP-GP2) and is a consultant for Acurex.

MGS is supported by a graduate student award, Jeanne Timmins Costello Award. ZGO is supported by the Fonds de recherche du Quebec-Sante (FRQS) Chercheurs-boursiers award and is a William Dawson Scholar. This study was supported by The Canadian Consortium on Neurodegeneration in Aging (CCNA), and by the GBA1-Canada initiative (G-Can - https://gba1can.org/), which is funded by The Hilary and Galen Weston Foundation and The Van Berkom family. This research used the NeuroHub infrastructure and was undertaken thanks in part to funding from the Canada First Research Excellence Fund, awarded through the Healthy Brains, Healthy Lives initiative at McGill University, Calcul Quebec and Compute Canada. This research has been conducted using the UK Biobank Resource under Application Number 45551. The UKBB cohort was accessed using NeuroHub (https://www.mcgill.ca/hbhl/neurohub).

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