Population-specific rare variants influence age at diagnosis in Korean inflammatory bowel disease

Cho, Mina; Shin, DongHwan; Yu, Jongwook; Cheon, Jae Hee; Kim, Ju Han

doi:2026.41.5.847

Korean J Intern Med > Volume 41(5); 2026 > Article

ORIGINAL ARTICLE

Korean J Intern Med. 2026;41(5):847-857. doi: https://doi.org/10.3904/kjim.2026.055

Population-specific rare variants influence age at diagnosis in Korean inflammatory bowel disease

Mina Cho¹, DongHwan Shin², Jongwook Yu², Jae Hee Cheon²

, and Ju Han Kim¹

¹Seoul National University Biomedical Informatics (SNUBI), Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, Korea
²Department of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea

Corresponding Author: Jae Hee Cheon , Tel: +82-2-2228-1990, Fax: +82-2-393-6884, Email: geniushee@yuhs.ac
Ju Han Kim , Tel: +82-2-740-8320, Fax: +82-2-747-8928, Email: juhan@snu.ac.kr

Received: January 28, 2026; Revised: April 6, 2026; Accepted: April 21, 2026.

Abstract

Background/Aims: Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is increasing in East Asia. Most known susceptibility loci, identified primarily in Europeans, remain insufficient to explain clinical heterogeneity in Asians. We performed whole-exome sequencing in Korean IBD patients to identify population-specific variants influencing age at diagnosis.
Methods: We analyzed 341 Korean IBD patients (192 CD, 149 UC) from three cohorts. Case-control analysis with external controls was confounded by platform heterogeneity, so we used a within-case Cox proportional hazards model instead. Variants were prioritized using a dual-threshold strategy. Gene-level analysis identified subtype-specific pathways, and disease progression was assessed in patients with longitudinal data (n = 206).
Results: We identified 12 novel rare variants (minor allele frequency < 0.01 in gnomAD) predominantly observed in East Asian populations. One variant in GSG1 (rs146166808) reached genome-wide significance (p = 3.39 × 10^-8); carriers showed accelerated disease onset and increased risk of aggressive progression (OR = 12.52, p = 0.050). Subtype-specific analyses identified two variants for CD (GSG1, CYP2D6) and five for UC (including IGLL1). Gene-level analysis revealed distinct genetic architectures: CD showed enrichment for axon guidance pathways (p = 0.000065), whereas UC showed enrichment for calcium signaling and tissue maintenance pathways (p = 0.00068).
Conclusions: We identified population-specific rare variants influencing disease onset and progression in Korean IBD. Distinct genetic architectures underlying CD and UC provide insight into IBD heterogeneity and potential therapeutic targets in this population.

Keywords: Inflammatory bowel disease ; Crohn’s disease ; Ulcerative colitis ; Exome sequencing ; Age of onset