Michelle Campbell1,2, Jun Wei3, Mikhail Attaar4,5, Hoover Wu4,5, Harry J Wong4,5, Michael B Ujiki4, Jianfeng Xu3. 1. Department of Surgery, University of Chicago Medical Center, Chicago, IL, USA. Campbell2@uchospitals.edu. 2. Department of Surgery, Northshore University HealthSystem, 2650 Ridge Ave, GCSI Suite B665, Evanston, IL, 60201, USA. Campbell2@uchospitals.edu. 3. Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, USA. 4. Department of Surgery, NorthShore University HealthSystem, Evanston, IL, USA. 5. Department of Surgery, University of Chicago Medical Center, Chicago, IL, USA.
Abstract
INTRODUCTION: Genetic contributions to hernia development are incompletely understood. This study performed the first comprehensive genome-wide association study (GWAS) for diaphragmatic hernia using a large population-based cohort in the UK Biobank (UKB). METHODS AND PROCEDURES: Two-stage GWAS (discovery and confirmation) was performed for diaphragmatic hernia in the UKB. Briefly, 275,549 and 91,850 subjects were randomly selected for association tests in Stages 1 and 2, respectively. Association tests between 8,568,156 SNPs (genotyped or imputed with MAF > 0.01) in the autosomal genome and diaphragmatic hernia were performed in Stage 1. SNPs with P < 1 × 10-5 were selected for confirmation in Stage 2, and those with P < 0.05 and the same direction of association as Stage 1 were selected for combined association testing; SNPs with combined P < 5 × 10-8 were considered GWAS-significant. LD clumping analysis identified genetically independent chromosomal regions (loci). A genetic risk score (GRS) measured the cumulative risk of independent SNPs in 91,849 additional subjects using odds ratios (ORs) from Stages 1 and 2. RESULTS: 36,351 patients were identified with diaphragmatic hernia (ICD-10 K44). In Stage 1 analysis, 2654 SNPs were associated (P < 1 × 10-5) with diaphragmatic hernia. Stage 2 analysis confirmed 338 SNPs (P < 0.05). In combined analysis, 245 SNPs reached GWAS significance (P < 5 × 10-8). LD clumping analysis revealed 14 independent loci associated with diaphragmatic hernia. Two loci have been previously associated with inguinal hernia at 2p16 (rs181661155) and 11p13 (rs5030123). eQTL analysis suggested genes CRLF1, UBA52, and CALD1 are also significantly associated with these loci. GRS showed significant increase in cases compared to controls (P < 1 × 10-16) and is associated with increased risk of diaphragmatic hernia (P < 1 × 10-7). CONCLUSIONS: We identified 245 SNPs at 14 susceptibility loci associated with diaphragmatic hernia in a large population-based cohort. These results offer insight into pathogenetic mechanisms of diaphragmatic hernia development and may be used in genetic risk scores for pre-operative risk-stratification and clinical prediction models.
INTRODUCTION: Genetic contributions to hernia development are incompletely understood. This study performed the first comprehensive genome-wide association study (GWAS) for diaphragmatic hernia using a large population-based cohort in the UK Biobank (UKB). METHODS AND PROCEDURES: Two-stage GWAS (discovery and confirmation) was performed for diaphragmatic hernia in the UKB. Briefly, 275,549 and 91,850 subjects were randomly selected for association tests in Stages 1 and 2, respectively. Association tests between 8,568,156 SNPs (genotyped or imputed with MAF > 0.01) in the autosomal genome and diaphragmatic hernia were performed in Stage 1. SNPs with P < 1 × 10-5 were selected for confirmation in Stage 2, and those with P < 0.05 and the same direction of association as Stage 1 were selected for combined association testing; SNPs with combined P < 5 × 10-8 were considered GWAS-significant. LD clumping analysis identified genetically independent chromosomal regions (loci). A genetic risk score (GRS) measured the cumulative risk of independent SNPs in 91,849 additional subjects using odds ratios (ORs) from Stages 1 and 2. RESULTS: 36,351 patients were identified with diaphragmatic hernia (ICD-10 K44). In Stage 1 analysis, 2654 SNPs were associated (P < 1 × 10-5) with diaphragmatic hernia. Stage 2 analysis confirmed 338 SNPs (P < 0.05). In combined analysis, 245 SNPs reached GWAS significance (P < 5 × 10-8). LD clumping analysis revealed 14 independent loci associated with diaphragmatic hernia. Two loci have been previously associated with inguinal hernia at 2p16 (rs181661155) and 11p13 (rs5030123). eQTL analysis suggested genes CRLF1, UBA52, and CALD1 are also significantly associated with these loci. GRS showed significant increase in cases compared to controls (P < 1 × 10-16) and is associated with increased risk of diaphragmatic hernia (P < 1 × 10-7). CONCLUSIONS: We identified 245 SNPs at 14 susceptibility loci associated with diaphragmatic hernia in a large population-based cohort. These results offer insight into pathogenetic mechanisms of diaphragmatic hernia development and may be used in genetic risk scores for pre-operative risk-stratification and clinical prediction models.
Authors: Lan Yu; Julia Wynn; Lijiang Ma; Saurav Guha; George B Mychaliska; Timothy M Crombleholme; Kenneth S Azarow; Foong Yen Lim; Dai H Chung; Douglas Potoka; Brad W Warner; Brian Bucher; Charles A LeDuc; Katherine Costa; Charles Stolar; Gudrun Aspelund; Marc S Arkovitz; Wendy K Chung Journal: J Med Genet Date: 2012-10 Impact factor: 6.318
Authors: Mauro Longoni; Frances A High; Hongjian Qi; Maliackal P Joy; Regis Hila; Caroline M Coletti; Julia Wynn; Maria Loscertales; Linshan Shan; Carol J Bult; Jay M Wilson; Yufeng Shen; Wendy K Chung; Patricia K Donahoe Journal: Hum Genet Date: 2017-03-16 Impact factor: 4.132
Authors: Lan Yu; Julia Wynn; Yee Him Cheung; Yufeng Shen; George B Mychaliska; Timothy M Crombleholme; Kenneth S Azarow; Foong Yen Lim; Dai H Chung; Douglas Potoka; Brad W Warner; Brian Bucher; Charles Stolar; Gudrun Aspelund; Marc S Arkovitz; Wendy K Chung Journal: Hum Genet Date: 2012-11-09 Impact factor: 4.132
Authors: J Wei; M Attaar; Z Shi; R Na; W K Resurreccion; S P Haggerty; S L Zheng; B T Helfand; M B Ujiki; J Xu Journal: Hernia Date: 2021-08-11 Impact factor: 2.920
Authors: Eric Jorgenson; Nadja Makki; Ling Shen; David C Chen; Chao Tian; Walter L Eckalbar; David Hinds; Nadav Ahituv; Andrew Avins Journal: Nat Commun Date: 2015-12-21 Impact factor: 14.919
Authors: Clare Bycroft; Colin Freeman; Desislava Petkova; Gavin Band; Lloyd T Elliott; Kevin Sharp; Allan Motyer; Damjan Vukcevic; Olivier Delaneau; Jared O'Connell; Adrian Cortes; Samantha Welsh; Alan Young; Mark Effingham; Gil McVean; Stephen Leslie; Naomi Allen; Peter Donnelly; Jonathan Marchini Journal: Nature Date: 2018-10-10 Impact factor: 49.962