Department of Surgery, University of Chicago Medical Center, Chicago, IL, USA.
Department of Surgery, Northshore University HealthSystem, 2650 Ridge Ave, GCSI Suite B665, Evanston, IL, 60201, USA.
Surg Endosc. 2022 Oct;36(10):7647-7651. doi: 10.1007/s00464-022-09064-6. Epub 2022 Sep 8.
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).
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 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 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.
36,351 patients were identified with diaphragmatic hernia (ICD-10 K44). In Stage 1 analysis, 2654 SNPs were associated (P < 1 × 10) with diaphragmatic hernia. Stage 2 analysis confirmed 338 SNPs (P < 0.05). In combined analysis, 245 SNPs reached GWAS significance (P < 5 × 10). 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) and is associated with increased risk of diaphragmatic hernia (P < 1 × 10).
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.
疝发展的遗传因素尚不完全清楚。本研究使用英国生物库（UKB）中的大型基于人群的队列进行了首次膈疝全基因组关联研究（GWAS）。
膈疝的两阶段 GWAS（发现和确认）在 UKB 中进行。简要地说，分别在第 1 阶段和第 2 阶段随机选择 275549 名和 91850 名受试者进行关联测试。在第 1 阶段，对常染色体基因组中 8568156 个 SNP（用 MAF > 0.01 进行基因分型或 imputed）与膈疝之间的关联进行了关联测试。在第 2 阶段中选择 P < 1×10 的 SNP 进行确认，选择 P < 0.05 且与第 1 阶段相同的方向的 SNP 进行联合关联测试；将联合 P < 5×10 的 SNP 视为 GWAS 显著。LD 聚类分析确定了遗传上独立的染色体区域（基因座）。遗传风险评分（GRS）使用来自第 1 阶段和第 2 阶段的比值比（OR）在 91849 名额外受试者中测量了独立 SNP 的累积风险。
确定了 36351 例膈疝患者（ICD-10 K44）。在第 1 阶段分析中，有 2654 个 SNP 与膈疝相关（P < 1×10）。第 2 阶段分析确认了 338 个 SNP（P < 0.05）。在联合分析中，有 245 个 SNP 达到了 GWAS 意义（P < 5×10）。LD 聚类分析揭示了与膈疝相关的 14 个独立基因座。两个基因座先前与腹股沟疝相关，位于 2p16（rs181661155）和 11p13（rs5030123）。eQTL 分析表明，CRLF1、UBA52 和 CALD1 基因也与这些基因座显著相关。GRS 显示病例组与对照组相比显着增加（P < 1×10），并且与膈疝风险增加相关（P < 1×10）。
我们在一个大型基于人群的队列中鉴定了 14 个与膈疝相关的 245 个 SNP 易感基因座。这些结果为膈疝发展的发病机制提供了深入的了解，并且可以用于遗传风险评分，以进行术前风险分层和临床预测模型。
