Susceptibility loci and polygenic architecture highlight population specific and common genetic features in inguinal hernias

Abstract

Background: The underlying pathology of inguinal hernia is still not fully known; thus, further investigations of genetic backgrounds is needed. Here, we aimed to identify genetic factors attributing to inguinal hernias and explore the polygenic architecture of which some components are population-specific, while others are more common among populations. Methods: We performed a genome-wide association study (GWAS) on subjects with inguinal hernias using BioBank Japan (BBJ) data with 1,983 cases and 172,507 controls, followed by a trans-ethnic meta-analysis with UK Biobank (UKBB) data. We performed downstream analyses in order to identify the mechanisms underlying inguinal hernias supported by genetic findings. Findings: We identified a locus closest to ELN, which encodes elastin, at the GWAS significant level. The transethnic meta-analysis revealed 23 additional significant loci, including five loci newly identified not significant in BBJ or UKBB GWAS: TGFB2, RNA5SP214/VGLL2, LOC646588, HMCN2, and ATP5F1CP1/CDKN3. Downstream analyses revealed the overlap of GWAS significant signals in extracellular components, including elastin fiber formation. We also found a highly shared polygenic architecture across different populations (trans-ethnic genetic-effect correlation = 077, standard error = 026) and population-specific lead variants in ELN, indicating the critical role of elastin in inguinal hernias. Interpretation: We identified a significant locus of the ELN gene in the Japanese population and five additional loci across different populations. Downstream analyses revealed highly shared genetic architectures across populations and highlighted the important roles of extracellular components in the development of inguinal hernias. These findings deepen our understanding of the mechanisms underlying inguinal hernia.

Sex-specific genetic variants associated with adult-onset inguinal hernia in a Taiwanese population

“…Genetic defects in any components of the inguinal canal, including collagen, microfibrils, elastin, abdominal wall muscles, and glycosaminoglycan elements of the extracellular matrix, could result in inguinal hernia formation. 19 A number of genes or risk loci associated with inguinal hernia were identified by candidate gene approach 12 and genome-wide association studies; 16 , 17 , 20 most of them were correlated with connective tissue homoeostasis, such as elastin (ELN). 17 Decreased tissue concentration of ELN was observed in inguinal hernia patients, 21 and it has been reported that variants in ELN gene are associated with inguinal hernia development.…”

“… 19 A number of genes or risk loci associated with inguinal hernia were identified by candidate gene approach 12 and genome-wide association studies; 16 , 17 , 20 most of them were correlated with connective tissue homoeostasis, such as elastin (ELN). 17 Decreased tissue concentration of ELN was observed in inguinal hernia patients, 21 and it has been reported that variants in ELN gene are associated with inguinal hernia development. 20 Epidermal growth factor-containing fibulin-like extracellular matrix protein 1 ( EFEMP1 ) belongs to the fibulin gene family, and it is crucial for ELN production and elastic fiber formation by regulating incorporation of elastin to the microfibril architecture.…”

“…Then, the Taiwan Biobank version 2 (TWBv2) array was used to perform next generation sequencing (NGS) for the participants, including 114,000 risk variants in 2,831 unusual disease genes selected from ClinVar, ACMG, GWAS Catalog, HGMD, locus-specific databases, and the published literature. 18 After literature review, we chose four available single nucleotide polymorphisms (SNP), namely, rs2009262, rs13091322, rs6991952, and rs3809060, for further analyses, which were previously reported by Jorgenson et al 16 and Hikino et al 17 Quality control of genotyping included an exclusion of SNPs if only one allele appeared in the study cohort; the total call rate < 95% or the total MAF < 0.01. In addition, SNPs significantly departing from the Hardy-Weinberg equilibrium (P < 1 × 10-4) were also excluded.…”

“…The primary aim of this study was to verify whether susceptibility loci (rs2009262, rs13091322, rs6991952, and rs3809060) previously reported in Europeans 16 , 17 contribute to inguinal hernia and comorbidities in the Taiwanese population. The secondary aim was to distinguish sex-specific risk factors for the development of inguinal hernia in a hospital-based cohort.…”

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

“…Previously, Jorgenson et al have identified four susceptibility loci for inguinal hernia alone (WT1, EFEMP1, EBF2 and ADAMTS6), each of which may result in aberrant elastic tissue homeostasis mediated via disordered expression of matrix metalloproteinases (MMPs) [13]. 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].…”