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Background: Knee Osteoarthritis (KOA) is a prevalent and debilitating condition affecting millions worldwide, yet its underlying etiology remains poorly understood. Recent advances in neuroimaging and genetic methodologies offer new avenues to explore the potential neuropsychological contributions to KOA. This study aims to investigate the causal relationships between brainwide morphometric variations and KOA using a genetic epidemiology approach. Method: Leveraging data from 36,778 UK Biobank participants for human brain morphometry and 487,411 UK Biobank participants for KOA, this research employed a two-sample Mendelian Randomization (TSMR) approach to explore the causal effects of 83 brain-wide volumes on KOA. The primary method of analysis was the Inverse Variance Weighted (IVW) and Wald Ratio (WR) method, complemented by MR Egger and IVW methods for heterogeneity and pleiotropy assessments. A significance threshold of p < 0.05 was set to determine causality. The analysis results were assessed for heterogeneity using the MR Egger and IVW methods. Brain-wide volumes with Q_pval < 0.05 were considered indicative of heterogeneity. The MR Egger method was employed to evaluate the pleiotropy of the analysis results, with brain-wide volumes having a p-value < 0.05 considered suggestive of pleiotropy. Results: Our findings revealed significant causal associations between KOA and eight brain-wide volumes: Left parahippocampal volume, Right posterior cingulate volume, Left transverse temporal volume, Left caudal anterior cingulate volume, Right paracentral volume, Left paracentral volume, Right lateral orbitofrontal volume, and Left superior temporal volume. These associations remained robust after tests for heterogeneity and pleiotropy, underscoring their potential role in the pathogenesis of KOA. Conclusion: This study provides novel evidence of the causal relationships between specific brain morphometries and KOA, suggesting that neuroanatomical variations might contribute to the risk and development of KOA. These findings pave the way for further research into the neurobiological mechanisms underlying KOA and may eventually lead to the development of new intervention strategies targeting these neuropsychological pathways. [ABSTRACT FROM AUTHOR]