Post Traumatic Osteoarthritis (PTOA) of the knee is osteoarthritis (OA) occurring specifically after a significant acute injury to the joint. Approximately 50% of people with significant knee joint injuries, such as anterior cruciate ligament (ACL) rupture, develop symptomatic radiographic OA within 10 years. Although impacts of the disease are well-described, there is little known about the genetic risk of developing OA after a knee injury relative to idiopathic OA. There is an unmet clinical need to understand the aetiology of PTOA, which will help us to understand, predict and prevent PTOA. In this Analysis Plan, we describe our methodological approach to performing a Genome Wide Association Study (GWAS) meta-analysis, developed by the Genetics of Osteoarthritis consortium (GO)-PTOA working group. We aim to determine if genetic variants associate with PTOA following a knee joint injury and understand whether these variants are similar to or different from those associated with idiopathic knee OA (iOA). Summary statistics from six international cohorts and biobanks will be included in the meta-analysis. We have harmonized an approach to identify cases of acute knee injury, knee PTOA cases as well as controls. Our three main objectives are to identify genetic variation associated with: 1) knee PTOA independent of knee iOA 2) knee PTOA compared with knee injured controls without OA 3) knee PTOA compared with controls over 40 years of age without injury or OA Although not part of our primary analysis, we also plan to identify genetic variation associated with the onset of knee PTOA in a time-to-event analysis in the future. Where resources allow, sensitivity analyses for all aims will be carried out, adjusting for body mass index (BMI). For case-control analyses, either a logistic regression or linear mixed model (LMM) will be used. For later time-to-event analysis, a matched case-control Cox Proportion Hazards (PH) regression model will be applied. Cohorts will share their summary statistics with the central analysis site conducting the single meta-analysis for each GWAS, which is likely to be carried out in either METAL or GWAMA. Findings from this work will potentially improve our understanding of PTOA pathogenesis and aetiology. Better understanding of genetic determinants could contribute to more accurate prognostic modelling and precision medicine in the future. Keywords: Osteoarthritis, Post-traumatic osteoarthritis, Genome Wide Analysis Study

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf<http://www.icmje.org/coi_disclosure.pdf>[url=%3E]. FW is an associate editor of Osteoarthritis & Cartilage. In the last 3 years she has received consulting fees from Pfizer. FW is chair of the PARIS Trial Oversight Committee (unremunerated). FW is Co-lead, UK NIHR Translational Research Collaboration, Common MSK Conditions workstream (unremunerated). KB is an associate editor of Knee Surgery, Sports Traumatology, Arthroscopy. KB is on the International editorial board for the Journal of Orthopaedics and Sports Physical Therapy. JS has received consultant fees from AstraZeneca, Schipher, Crealta/Horizon, Medisys, Fidia, PK Med, Two labs Inc, Adept Field Solutions, Clinical Care options, Clearview healthcare partners, Putnam associates, Focus forward, Navigant consulting, Spherix, MedIQ, Jupiter Life Science, UBM LLC, Trio Health, Medscape, WebMD, and Practice Point communications, the National Institutes of Health, and the American College of Rheumatology. JS has received institutional research support from Zimmer Biomet Holdings. JS received food and beverage payments from Intuitive Surgical Inc/Philips Electronics North America. JS owns stock options in Atai life sciences, Kintara therapeutics, Intelligent Biosolutions, Acumen pharmaceutical, TPT Global Tech, Vaxart pharmaceuticals, Atyu biopharma, Adaptimmune Therapeutics, GeoVax Labs, Pieris Pharmaceuticals, Enzolytics Inc, Seres Therapeutics, Tonix Pharmaceuticals Holding Corp, and Charlotte's Web Holdings, Inc. JS previously owned stock options in Amarin, Viking and Moderna pharmaceuticals. JS is on the speaker's bureau of Simply Speaking. JS was a member of the executive of Outcomes Measures in Rheumatology (OMERACT), an organization that develops outcome measures in rheumatology and receives arms-length funding from 8 companies. JS serves on the FDA Arthritis Advisory Committee. JS is the co-chair of the Veterans Affairs Rheumatology Field Advisory Board (FAB). JS is the editor and the Director of the University of Alabama at Birmingham (UAB) Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis. JS previously served as a member of the following committees: member, the American College of Rheumatology's (ACR) Annual Meeting Planning Committee (AMPC) and Quality of Care Committees, the Chair of the ACR Meet-the-Professor, Workshop and Study Group Subcommittee and the co-chair of the ACR Criteria and Response Criteria subcommittee. No other authors declare a conflict of interest.

Imperial College London funding and coordination of the group FW and RK are funded by a UK Research and Innovation (UKRI) Future Leaders Fellowship to FW, (MR/S016538/1 and MR/S016538/2). Oxford funding LJD is supported by Wellcome Trust grant 208750/Z/17/Z. VA Million Veteran Program (MVP) funding This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by award #I01RX002745. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. Estonian Biobank (EstBB) funding This study was funded by European Union through the European Regional Development Fund Project No. 2014-2020.4.01.15-0012 GENTRANSMED and the Estonian Research Council grant PUT (PRG1911). Data analysis was carried out in part in the High-Performance Computing Center of University of Tartu. The activities of the EstBB are regulated by the Human Genes Research Act, which was adopted in 2000 specifically for the operations of the EstBB. Individual level data analysis in the EstBB was carried out under ethical approval [1.1-12/624] from the Estonian Committee on Bioethics and Human Research (Estonian Ministry of Social Affairs), using data according to release application [N05] from the Estonian Biobank University of Iceland Work was supported by a payment made to the University of Iceland research account. No other authors declare a funding.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The future work proposed within this protocol does not require ethical approval, as it utilises summary statistics only (rather than individual participant data) from existing approved studies.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

No data has been produced