10.18710/8LC9EA Alam, Mohammad Sayeef Mohammad Sayeef Alam https://orcid.org/0000-0002-1478-5975 NTNU – Norwegian University of Science and Technology Thomas, Laurent F. Laurent F. Thomas NTNU – Norwegian University of Science and Technology Brumpton, Ben M. Ben M. Brumpton NTNU – Norwegian University of Science and Technology Hveem, Kristian Kristian Hveem NTNU – Norwegian University of Science and Technology Lundin, Knut E. A. Knut E. A. Lundin UiO - University in Oslo Withoff, Sebo Sebo Withoff UMCG - University Medical Center Groningen Jonkers, Iris H. Iris H. Jonkers UMCG - University Medical Center Groningen Sollid, Ludvig M. Ludvig M. Sollid UiO - University in Oslo Hjort, Rebecka Rebecka Hjort NTNU – Norwegian University of Science and Technology Ness-Jensen, Eivind Eivind Ness-Jensen NTNU – Norwegian University of Science and Technology DataverseNO 2025 Medicine, Health and Life Sciences celiac disease gwas non-HLA gluten NTNU – Norwegian University of Science and Technology NTNU – Norwegian University of Science and Technology Alam, Mohammad Sayeef Mohammad Sayeef Alam NTNU – Norwegian University of Science and Technology Alam, Mohammad Sayeef Mohammad Sayeef Alam Ness-Jensen, Eivind Eivind Ness-Jensen Hjort, Rebecka Rebecka Hjort Sollid, Ludvig M. Ludvig M. Sollid Lundin, Knut E. A. Knut E. A. Lundin Jonkers, Iris H. Iris H. Jonkers Withoff, Sebo Sebo Withoff 2025-02-11 2025-08-29 10.1038/S41598-025-04421-6 10.18710/8LC9EA/DB9ZJE 10.18710/8LC9EA/FFJIZX 10.18710/8LC9EA/MAWPL3 272989025 205743 6599 application/zip application/pdf text/plain 1.0 Creative Commons CC0 1.0 Universal Public Domain Dedication. Previous studies have uncovered genetic loci associated with celiac disease (CeD) within both the human leukocyte antigen (HLA) and non-HLA regions. However, half of the heritability remains unexplained. This study aimed to identify novel loci associated with CeD in a general adult population screened for the disease, mitigating the likely selection bias observed in previous case-control studies. The study utilized data from the fourth Trøndelag Health Study (HUNT4) in Norway, where 52,358 adults were screened for CeD using serology, identifying 465 previously undiagnosed biopsy-confirmed cases. Additionally, 377 previously diagnosed cases were identified through hospital journal searches and registry data. Genotyping of 373,185 single nucleotide polymorphisms was performed on all participant using four Illumina HumanCoreExome arrays. Imputation, using the Haplotype Reference Consortium panel, resulted in approximately 24.9 million variants, post quality control. A genome-wide association study was performed using SAIGE, and functional mapping and pathway enrichment analysis was conducted using FUMA. All except one of the 42 known autosomal loci were present in the data, of which seven reached the suggestive significance threshold (P ≤ 5 × 10−6). Thirteen independent novel associations were observed (P ≤ 5× 10−8), with the 5p15.33 locus showing the highest potential for a true association with CeD, warranting further studies to validate the findings. Notably, the IRX1 gene, located close to the 5p15.33 locus has also been associated with rheumatoid arthritis, suggesting a new shared autoimmune locus. R, 4.1.2 Plink, 1.9 The Trøndelag Health Study (HUNT) has invited individuals aged 13-100 years to four surveys between 1984 and 2019. Comprehensive data from more than 140,000 individuals having participated at least once and biological material from 78,000 individual are collected. The data are stored in HUNT databank and biological material in HUNT biobank. HUNT Research Centre has permission from the Norwegian Data Inspectorate to store and handle these data. The key identification in the database is the personal identification number given to all Norwegians at birth or immigration, whilst de-identified data are sent to researchers upon approval of a research protocol by the Regional Ethical Committee and HUNT Research Centre. To protect participants’ privacy, HUNT Research Centre aims to limit storage of data outside HUNT databank and cannot deposit data in open repositories. HUNT databank has precise information on all data exported to different projects and are able to reproduce these on request. There are no restrictions regarding data export given approval of applications to HUNT Research Centre. For more information see: http://www.ntnu.edu/hunt/data Norway, Nord Trøndelag, Trondheim Research Council of Norway #288308 Liaison Committee between NTNU and the Central Norway Regional Health Authority #17/38297 Liaison Committee between NTNU and the Central Norway Regional Health Authority #18/42795 Liaison Committee between NTNU and the Central Norway Regional Health Authority #23/32925 NIH - National Institutes of Health NIH R35 HL135824-03