Purpose: Familial aggregation is known for both hernia development and recurrence. To date, only one genome-wide association study (GWAS) limited to inguinal hernia has been reported that identified four risk-associated loci. We aim to investigate polygenic architecture of abdominal wall hernia development and recurrence.
Methods: A GWAS was performed in 367,394 subjects from the UK Biobank to investigate the polygenic architecture of abdominal wall hernia subtypes (inguinal, femoral, umbilical, ventral) and identify specific single nucleotide polymorphisms (SNPs) that are associated with their risk. Expression quantitative trait loci (eQTL) analysis was performed to identify genes whose expression levels are associated with these SNPs. A genetic risk score (GRS) was used to assess the cumulative effect of multiple independent risk-associated SNPs on hernia development and recurrence in independent subjects (n = 82,064).
Results: Heritability (h2) was 0.12, 0.06, 0.16, and 0.07 for inguinal, femoral, umbilical, and ventral hernias, respectively. A high-level of genetic correlation (rg) was found among these subtypes of hernia. We confirmed the aforementioned four loci and identified 57 novel loci (P < 5 × 10-8), including 55, 3, 5, and 3 loci for inguinal, femoral, umbilical, and ventral hernias, respectively. Significantly different expression levels between risk/reference alleles of SNPs were found for 145 genes, including TGF-β2 and AIG1 for inguinal hernia risk and CALD1 for umbilical hernia risk. Finally, higher GRS deciles were significantly associated with increased risk for hernia development (Ptrend = 3.33 × 10-38) and recurrent hernia repair surgery (Ptrend = 3.64 × 10-14).
Conclusion: These novel results have potential biological and clinical implications for hernia management in high-risk patients.
Keywords: Genome-wide association study; Hernia; Pathway analysis; Polygenic risk score; eQTL.
© 2021. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.