Genetic correlations among diaphragmatic, femoral, inguinal, ventral, and umbilical hernias and identification of their candidate genes

OBJECTIVE: Different subtypes of hernia exhibit significant familial aggregation. However, the genetic correlations among different hernia subtypes, as well as their shared and subtype-specific candidate genes still remain unclear. METHODS: Using genome-wide association study (GWAS) data from the FinnGen consortium, we quantified genetic correlations (rg) among diaphragmatic (16 034 cases), inguinal (43 066 cases), femoral (1 660 cases), and hernia of abdominal wall (21 210 cases, including umbilical and ventral hernias) by linkage disequilibrium score regression. Mendelian randomization (MR) analyses were performed using 15 695 expression quantitative trait loci (eQTL) as exposures and hernia GWAS data as outcomes. Multiple testing was controlled using the false discovery rate (q < 0.05), and findings were further prioritized through Bayesian colocalization. Shared candidate genes were validated using fibroblast eQTL data from GTEx V10 and protein quantitative trait loci data from the UK Biobank. RESULTS: Significant genetic correlations were observed across all hernia subtypes (P < 0.01), with the strongest correlation between ventral and umbilical hernias (rg = 0.78), while diaphragmatic hernia exhibited weaker correlations with other subtypes (rg = 0.26-0.48). MR analyses using blood and fibroblast-derived eQTL data identified BMP6, MYCBPAP, and ZNF75A as candidate genes shared across multiple hernia subtypes. Proteomic validation further revealed that elevated BMP6 protein levels were associated with a reduced risk for all hernia subtypes. CONCLUSION: This study reveals a shared genetic basis among common hernia subtypes and identifies three shared candidate genes (BMP6, MYCBPAP, and ZNF75A). Elevated BMP6 protein levels were associated with a reduced risk of multiple hernia types. These findings provide new insights into the genetic correlations and potential pathogenic mechanisms underlying hernia. Future functional studies are needed to elucidate the roles of these genes in abdominal wall tissue.