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Abstract Osteoarthritis is the third most rapidly growing health condition associated with disability, after dementia and diabetes¹. By 2050, the total number of patients with osteoarthritis is estimated to reach 1 billion worldwide². As no disease-modifying treatments exist for osteoarthritis, a better understanding of disease aetiopathology is urgently needed. Here we perform a genome-wide association study meta-analyses across up to 489,975 cases and 1,472,094 controls, establishing 962 independent associations, 513 of which have not been previously reported. Using single-cell multiomics data, we identify signal enrichment in embryonic skeletal development pathways. We integrate orthogonal lines of evidence, including transcriptome, proteome and epigenome profiles of primary joint tissues, and implicate 700 effector genes. Within these, we find rare coding-variant burden associations with effect sizes that are consistently higher than common frequency variant associations. We highlight eight biological processes in which we find convergent involvement of multiple effector genes, including the circadian clock, glial-cell-related processes and pathways with an established role in osteoarthritis (TGFβ, FGF, WNT, BMP and retinoic acid signalling, and extracellular matrix organization). We find that 10% of the effector genes express a protein that is the target of approved drugs, offering repurposing opportunities, which can accelerate translation. 

Abstract. Chemical ionization mass spectrometry (CIMS) techniques have becomeprominent methods for sampling trace gases of relatively low volatility.Such gases are often referred to as being “sticky”, i.e., havingmeasurement artifacts due to interactions between analyte molecules andinstrument walls, given their tendency to interact with wall surfaces viaabsorption or adsorption processes. These surface interactions can impactthe precision, accuracy, and detection limits of the measurements. Weintroduce a low-pressure ion–molecule reaction (IMR) region primarily builtfor performing iodide-adduct ionization, though other adduct ionizationschemes could be employed. The design goals were to improve upon previouslow-pressure IMR versions by reducing impacts of wall interactions at lowpressure while maintaining sufficient ion–molecule reaction times. Chambermeasurements demonstrate that the IMR delay times (i.e., magnitude of wallinteractions) for a range of organic molecules spanning 5 orders ofmagnitude in volatility are 3 to 10 times lower in the new IMR compared toprevious versions. Despite these improvements, wall interactions are stillpresent and need to be understood. To that end, we also introduce aconceptual framework for considering instrument wall interactions and ameasurement protocol to accurately capture the time dependence of analyteconcentrations. This protocol uses short-duration, high-frequencymeasurements of the total background (i.e., fast zeros) during ambientmeasurements as well as during calibration factor determinations. Thisframework and associated terminology applies to any instrument andionization technique that samples compounds susceptible to wallinteractions.