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

• Main Authors: Keiko Hikino, M.D., Ph.D, Masaru Koido, Ph.D., Kohei Tomizuka, B.S., Xiaoxi Liu, Ph.D., Yukihide Momozawa, D.V.M., Ph.D., Takayuki Morisaki, M.D., Ph.D., Yoshinori Murakami, M.D., Ph.D., The Biobank Japan Project, Taisei Mushiroda, Ph.D., Chikashi Terao, M.D., Ph.D.
• Format: Article
• Language: English
• Published: Elsevier 2021-08-01
• Series: EBioMedicine
• Subjects: inguinal hernia; genome-wide association studies; trans-ethnic meta-analysis; polygenic architecture; BioBank Japan
• Online Access: http://www.sciencedirect.com/science/article/pii/S235239642100325X

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 trans-ethnic 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 = 0•77, standard error = 0•26) 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. Funding: The Japan Agency for Medical Research and Development (AMED) (Grant Number: JP19km0605001)