Aims:　Prior　evidence　has　shown　a　significant　link　between　inflammation　and　the　development　of　myocarditis.　This　study　aimed　to　investigate　the　causal　relationship　between　inflammation-related　genes　(IRGs)　and　myocarditis.　Methods　and　results:　In　this　study,　the　causal　relationship　between　167　IRGs　and　myocarditis　were　investigated　using　datasets　from　the　Gene　Set　Enrichment　Analysis　and　Integrative　Epidemiology　Unit　open　genome-wide　association　study　(IEU　OpenGWAS)　databases.　The　GWAS　data　(finn-b-I9　MYOCARD)　contained　single　nucleotide　polymorphisms　(SNPs)　data　from　117 755　myocarditis　samples　(16 379 455　SNPs,　829　cases　vs.　116 926　controls).　Five　algorithms　[MR-Egger,　weighted　median,　inverse　variance　weighted　(IVW),　simple　mode,　and　weighted　mode　regression]　were　employed　for　the　MR　analysis,　with　IVW　as　the　primary　method,　and　sensitivity　analysis　was　conducted.　Subcellular　localization　and　protein–protein　interaction　(PPI)　network　analyses　were　performed　for　selected　biomarkers.　Results　were　verified　in　ebi-a-GCST90018882　(24 180 570　SNPs,　633　cases　vs.　427 278　controls)　and　finn-b-I9　MYOCARD　EXNONE　(16 380 466　SNPs,　829　cases　vs.　217 963　controls)　to　enhance　reliability.　Results:　IRF7　and　ADORA2B　were　shown　to　be　two　exposure　factors　after　screening.　Univariable　MR　(UVMR)　analysis　revealed　that　IRF7　was　a　risk　factor　for　myocarditis　[IVW:　odd　ratio　(OR) = 1.041,　95%　confidence　interval　(CI) = 1.018–1.955,　P = 0.039],　while　ADORA2B　was　a　protective　factors　for　myocarditis　(IVW:　OR = 0.799,　95%　CI = 0.640–0.997,　P = 0.047).　Sensitivity　analysis　confirmed　the　robustness　of　these　findings.　Multivariable　MR　(MVMR)　analysis　further　demonstrated　a　direct　causal　role　of　ADORA2B　in　preventing　myocarditis.　Subcellular　localization　analysis　indicated　predominant　cytoplasmic　expression　and　limited　mitochondrial　expression　for　both　genes.　The　results　of　PPI　analysis　showed　that　20　genes　were　predicted　to　be　associated　with　IRF7　function,　such　as　response　to　type　I　interferon,　pattern　recognition　receptor　signalling　pathway,　and　toll-like　receptor　signalling　pathway.　The　results　in　finn-b-I9　MYOCARD　EXNONE　were　consistent　with　MR　analysis.　Conclusions:　The　findings　indicated　there　was　a　causal　connection　between　IRGs　(IRF7　and　ADORA2B)　and　myocarditis,　which　offered　a　crucial　point　of　reference　and　guidance　for　future　studies　and　myocarditis　treatment.　©　2024　The　Author(s).　ESC　Heart　Failure　published　by　John　Wiley　&　Sons　Ltd　on　behalf　of　European　Society　of　Cardiology.