Integrative Transcriptome-Wide Association Study and Mendelian Randomization Identify LYNX1 and MS4A14 as Therapeutic...

Osteomyelitis is a severe infectious disease characterized by profound inflammation of the bone and bone marrow and is predominantly caused by bacterial pathogens such as Staphylococcus aureus (S. aureus). However, current treatment regimens are significantly hindered by the emergence of antibiotic resistance and recurrent infections, driven by robust biofilm formation and intracellular bacterial persistence. Thus, there is an urgent need to identify novel therapeutic targets beyond conventional antimicrobials. An integrative computational approach combining a transcriptome-wide association study (TWAS) with summary-based Mendelian randomization (SMR) analysis was applied to systematically identify causal susceptibility genes underlying osteomyelitis. Large-scale genetic variants were leveraged as instrumental variables to predict gene expression across tissues, enabling the exploration of causal associations between these targets and disease risk. The integrative framework identified LYNX1 and MS4A14 as key candidate genes and potential therapeutic targets. Specifically, LYNX1 was associated with increased susceptibility to osteomyelitis, whereas MS4A14 exhibited potential protective properties. These findings highlight the regulatory roles of these genes in host immune response and inflammatory modulation during bone infection. This study bridges the gap between genome-wide association findings and biological interpretation, advancing the understanding of the genetic basis of osteomyelitis and supporting the development of targeted precision medicine strategies to enhance host defense and overcome therapeutic resistance.