Identification of Shared Genetic Loci Associated With Inflammatory Bowel Disease, Ischemic Heart Disease, and Atrial Fibrillation and Flutter

ABSTRACT The occurrence of ischemic heart disease (IHD), atrial fibrillation, and flutter demonstrates certain associations with inflammatory bowel disease (IBD), warranting further exploration at the genetic architecture level. This study focused on genome‐wide association study (GWAS) data of IHD, atrial fibrillation and flutter, and IBD, analyzing from two dimensions: genetic correlation and shared locus identification. Initially, linkage disequilibrium score regression and genetic covariance analyzer were utilized to assess the overall genetic correlations. Subsequently, the association patterns of local genomic regions were determined using Local Ancestry Variance Association (LAVA) analysis. Mendelian randomization (MR) was employed to assess causal effects. The genetic overlap among different traits was analyzed based on the statistical framework of conditional/conjunctional false discovery rate (cond/conjFDR). Finally, shared loci across these traits were identified by integrating conjFDR analysis with GWAS multi‐trait analysis (MTAG). At the genomic level, significant overall correlations were observed among IHD, atrial fibrillation and flutter, and IBD and Crohn's disease (CD), while associations with ulcerative colitis appeared less pronounced. At the local level, IHD and IBD (including subtypes) showed significant associations in multiple regions. However, atrial fibrillation and flutter exhibited local associations only in the context of CD. Through conjFDR analysis, the genetic overlap across these diseases was validated. Additionally, several shared genetic loci were identified by integrating conjFDR and MTAG analyses, with genes confirmed in both IHD and IBD (including subtypes), such as SMAD3 , PLCG2 , ZNF831 , PTPN22 , RP11‐136O12.2 , and RP11‐449I17.5 . Moreover, six common genes were identified in the analysis between atrial fibrillation and flutter and IBD (including subtypes), such as ZMIZ1 , MTHFS , ERAP2 , GNA12 , and RP1‐15D23.2 . This study offers empirical evidence of the genetic association between IHD, atrial fibrillation and flutter, and IBD comorbidity, providing new insights for cases where IBD co‐occurs with IHD or atrial fibrillation and flutter.