Multi-tissue transcriptome-wide association study identifies novel candidate genes and pleiotropy effects across four abdominal hernia subtypes

Dima L Chaar; Chen Jiang; Brandon Cowan; Sahil Patel; Mark Kvale; Jie Yin; Rouzbeh Mostaedi; Nadav Ahituv; Eric Jorgenson; Thomas J Hoffmann; Hélène Choquet

doi:10.1016/j.xhgg.2025.100436

Multi-tissue transcriptome-wide association study identifies novel candidate genes and pleiotropy effects across four abdominal hernia subtypes

HGG Adv. 2025 Apr 9;6(3):100436. doi: 10.1016/j.xhgg.2025.100436. Online ahead of print.

Authors

Affiliations

¹ Division of Research, Kaiser Permanente Northern California (KPNC), Pleasanton, CA 94588, USA.
² University of California, San Francisco (UCSF)-East Bay General Surgery, Oakland, CA 94602, USA.
³ Division of Research, Kaiser Permanente Northern California (KPNC), Pleasanton, CA 94588, USA; Institute for Human Genetics, UCSF, San Francisco, CA 94143, USA.
⁴ KPNC, Department of Surgery, Richmond Medical Center, Richmond, CA 94801, USA.
⁵ Institute for Human Genetics, UCSF, San Francisco, CA 94143, USA; Department of Bioengineering and Therapeutic Sciences, UCSF, San Francisco, CA 94143, USA.
⁶ Regeneron Genetics Center, Tarrytown, NY 10591, USA.
⁷ Institute for Human Genetics, UCSF, San Francisco, CA 94143, USA; Department of Epidemiology and Biostatistics, UCSF, San Francisco, CA 94158, USA.
⁸ Division of Research, Kaiser Permanente Northern California (KPNC), Pleasanton, CA 94588, USA; Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, CA 91101, USA. Electronic address: helene.choquet@kp.org.

Abstract

Abdominal hernias are caused by the protrusion of an organ or tissue through a weakened abdominal wall. Genome-wide association studies (GWASs) have identified 81 genetic susceptibility loci for different hernia subtypes, with 26 loci associated with more than one hernia type; however, additional work is needed to prioritize causal genes at known GWAS loci, identify novel ones, and characterize shared genetic effects across hernia subtypes. We conduct transcriptome-wide association study (TWAS) analyses of four hernia subtypes (i.e., inguinal, umbilical, ventral, femoral) using GWAS summary statistics from up to 57,291 hernia cases and 436,717 controls of European ancestry. Our TWAS, which leveraged imputed gene expression from 54 tissues, identifies 211 unique genes, of which 85 did not overlap with known hernia-associated loci. We also investigate patterns of pleiotropy and identify four genes (LYPLAL1-AS1, RIMKLBP2, AL513283.1, and EFEMP1) associated with all four hernia subtypes. Our findings enhance understanding of transcriptomic mechanisms through which hernias develop.

Keywords: abdominal hernia; femoral hernia; genetics; genome-wide association study; genomics; inguinal hernia; multi-tissue; transcriptome-wide association study; umbilical hernia; ventral hernia.