Identification of fifty-seven novel loci for abdominal wall hernia development and their biological and clinical implications: results from the UK Biobank

Abstract

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 (h 2 ) was 0.12, 0.06, 0.16, and 0.07 for inguinal, femoral, umbilical, and ventral hernias, respectively. A high-level of genetic correlation (r g ) 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 (P trend = 3.33 × 10 -38 ) and recurrent hernia repair surgery (P trend = 3.64 × 10 -14 ). Conclusion These novel results have potential biological and clinical implications for hernia management in high-risk patients.

Genetic analyses identify evidence for a causal relationship between Ewing sarcoma and hernias

“…Although the sample size for ventral hernia is relatively small, we observed that its genetic correlation was strong with multiple hernias. We noted that some correlation estimates were quite different from what was previously reported—for example, the reported genetic correlation between inguinal hernia and ventral hernia was 0.16; 20 however, it was estimated to be 0.53 in our analyses. The difference could be driven by the larger number of cases in our analyses.…”

Shared genetic architecture of hernias: A genome-wide association study with multivariable meta-analysis of multiple hernia phenotypes

“…Jorgenson and colleagues previously identified 4 inguinal hernia susceptibility loci purported to result in reduced MMP activity: WT1, EFEMP1, EBF2 and ADAMTS6 [13]. Recently, Wei et al replicated these associations and further implicated AIG1 and CALD1, which were identified as biologically relevant genes in their individual GWAS's of hernia phenotypes [15]. We have extended these results to focus on the shared biology of abdominal wall hernias.…”

“…The 1q41 locus (ZC3H11B) was strongly associated across three individual hernia phenotypes, the combined hernia cohorts, and importantly was also prioritised in metaUSAT meta-analysis. ZC3H11B, a zinc finger CCH domain-containing protein, was previously identified by Wei et al [15] in association with inguinal, femoral, umbilical and ventral hernia. ZC3H11B has also been associated with myopia endophenotypes, including axial length, refractive error, and corneal astigmatism [23].…”

“…A further trans-ethnic GWAS meta-analysis of inguinal hernia identified five further loci including TGFB2, HMCN2 and CDKN3 [14]. Wei et al attempted to characterise the polygenetic architecture of hernia using individual GWAS analysis of patients with either inguinal, femoral, umbilical or ventral hernia, identifying 57 loci, highlighting AIG1 and CALD1 as candidate genes for shared hernia susceptibility [15]. Interestingly, to our knowledge, GWAS of hiatus hernia has previously not been reported.…”

Personalized medicine in a community health system: the NorthShore experience

“…The development and clinical implementation of polygenic risk score (PRS) is a core translational research focus of PMED. Initial efforts focused on prostate cancer PRS and its clinical validity in multiple ancestral populations ( Shi et al, 2021 ; Shi et al, 2022 ) and then expanded to additional conditions ( Ahmed et al, 2022 ; Wei et al, 2022a ; Glaser et al, 2022 ; Billings et al, 2023 ; Patel et al, 2023 ; Shi et al, 2023 ), including other cancer types ( Shi et al, 2019 ; Northcutt et al, 2021 ; Wei et al, 2022b ). Recently, our efforts have centered on the clinical implementation of PRS.…”