{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T01:13:06Z","timestamp":1788311586608,"version":"build-2803163510"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"11-12","license":[{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T00:00:00Z","timestamp":1759104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"NTNU Norwegian University of Science and Technology"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Hum. Genet."],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>A large proportion of individuals with celiac disease (CeD) remain undiagnosed, often presenting at an older age of onset or with non-classical symptoms compared to diagnosed cases. Such heterogeneity might be related to genetic factors. The aim was to utilize a CeD-screened adult population to compare the genetic variants in known and newly diagnosed cases. In the fourth wave of the population-based Tr\u00f8ndelag Health Study (HUNT4) 826 CeD and 51,516 non-CeD individuals were included. Medical registries identified 361 previously diagnosed cases, while screening identified 465 new cases. A validated polygenic risk score (PRS) was used to assess the genetic risk of CeD among the two case groups versus non-CeD individuals. Additional genetic variants not included in the PRS were also analyzed. The PRS distinguished cases from non-cases with high accuracy (AUROC: 85% for known cases, 83% for new cases). The genetic variation explained by the PRS was similar for known and new cases (17.1% versus 14.5%). The odds ratio for being in the highest genetic risk group (top 10%) was 22.7 (95% CI 14.1\u201336.4) for known cases and 18.6 (95% CI 12.4\u201327.9) for new cases versus the median group (40%-60%). Differences in effect size among specific genome-wide variants were observed but were not significantly associated with CeD. A validated PRS showed significant genetic difference between CeD cases and the general population, with similar association in both known and newly diagnosed cases. This suggests that genetic architectures of the two groups are comparable, implying that other non-genetic factors may drive CeD in adults.<\/jats:p>","DOI":"10.1007\/s00439-025-02778-2","type":"journal-article","created":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T06:24:30Z","timestamp":1759127070000},"page":"1071-1078","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Genetic differences between diagnosed and undiagnosed Celiac disease: a population-based study"],"prefix":"10.1007","volume":"144","author":[{"given":"Mohammad Sayeef","family":"Alam","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke N.","family":"Wolford","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristian","family":"Hveem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Knut E. A.","family":"Lundin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebo","family":"Withoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris H.","family":"Jonkers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ludvig M.","family":"Sollid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecka","family":"Hjort","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eivind","family":"Ness-Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,29]]},"reference":[{"issue":"5","key":"2778_CR1","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1177\/2050640619844125","volume":"7","author":"A Al-Toma","year":"2019","unstructured":"Al-Toma A, Volta U, Auricchio R, Castillejo G, Sanders DS, Cellier C et al (2019) European society for the study of Coeliac disease (ESsCD) guideline for coeliac disease and other gluten-related disorders. United Eur Gastroenterol J 7(5):583\u2013613","journal-title":"United Eur Gastroenterol J"},{"issue":"1","key":"2778_CR2","doi-asserted-by":"publisher","first-page":"19764","DOI":"10.1038\/s41598-025-04421-6","volume":"15","author":"MS Alam","year":"2025","unstructured":"Alam MS, Thomas L, Brumpton B, Hveem K, Lundin KEA, Withoff S et al (2025) Population screening of adults identifies novel genetic variants associated with Celiac disease. Sci Rep 15(1):19764","journal-title":"Sci Rep"},{"issue":"1","key":"2778_CR3","doi-asserted-by":"publisher","first-page":"e80","DOI":"10.1093\/ije\/dyac095","volume":"52","author":"BO \u00c5svold","year":"2023","unstructured":"\u00c5svold BO, Langhammer A, Rehn TA, Kjelvik G, Gr\u00f8ntvedt TV, S\u00f8rgjerd EP et al (2023) Cohort profile update: the HUNT study, Norway. Int J Epidemiol 52(1):e80\u201391","journal-title":"Int J Epidemiol"},{"issue":"4","key":"2778_CR4","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1038\/ng.543","volume":"42","author":"PCA Dubois","year":"2010","unstructured":"Dubois PCA, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A et al (2010) Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42(4):295\u2013302","journal-title":"Nat Genet"},{"issue":"6","key":"2778_CR5","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1038\/ng.3268","volume":"47","author":"J Gutierrez-Achury","year":"2015","unstructured":"Gutierrez-Achury J, Zhernakova A, Pulit SL, Trynka G, Hunt KA, Romanos J et al (2015) Fine mapping in the MHC region accounts for 18% additional genetic risk for Celiac disease. Nat Genet 47(6):577\u2013578","journal-title":"Nat Genet"},{"issue":"5","key":"2778_CR6","doi-asserted-by":"publisher","first-page":"S","DOI":"10.1016\/S0016-5085(24)02149-8","volume":"166","author":"R Hjort","year":"2024","unstructured":"Hjort R, Andersen IL, Lukina P, Hveem K, Lundin KEA, Sollid LM et al (2024) Mapping of HLA-DQ haplotypes in adults with coeliac disease in a large, screened population\u2014results from the HUNT study. Gastroenterology 166(5):S\u2013728","journal-title":"Gastroenterology"},{"issue":"3","key":"2778_CR7","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1111\/apt.12373","volume":"38","author":"JY Kang","year":"2013","unstructured":"Kang JY, Kang AHY, Green A, Gwee KA, Ho KY (2013) Systematic review: worldwide variation in the frequency of coeliac disease and changes over time. Aliment Pharmacol Ther 38(3):226\u2013245","journal-title":"Aliment Pharmacol Ther"},{"key":"2778_CR8","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.clinbiochem.2022.05.010","volume":"107","author":"RA Klaasen","year":"2022","unstructured":"Klaasen RA, Warren DJ, Iversen R, Bolstad N, Andersen IL, Mj\u00f8nes P et al (2022) The development and validation of a high-capacity serological assay for Celiac disease. Clin Biochem 107:13\u201318","journal-title":"Clin Biochem"},{"key":"2778_CR9","doi-asserted-by":"crossref","unstructured":"Ludvigsson JF, Leffler DA, Bai JC, Biagi F, Fasano A, Green PHR et al (2013) The Oslo definitions for coeliac disease and related terms. Gut. Available from: https:\/\/gut.bmj.com\/content\/62\/1\/43?62\/1\/43r62\/1\/43","DOI":"10.1136\/gutjnl-2011-301346"},{"issue":"1","key":"2778_CR10","doi-asserted-by":"publisher","first-page":"e077131","DOI":"10.1136\/bmjopen-2023-077131","volume":"14","author":"P Lukina","year":"2024","unstructured":"Lukina P, Andersen IL, Eggen PT, Mj\u00f8nes PG, R\u00f8nne E, Bolstad N et al (2024) Coeliac disease in the Tr\u00f8ndelag health study (HUNT), norway, a population-based cohort of Coeliac disease patients. BMJ Open 14(1):e077131","journal-title":"BMJ Open"},{"key":"2778_CR11","doi-asserted-by":"publisher","unstructured":"Lukina P, Andersen IL, Klaasen RA, Warren DJ, Bolstad N, Mj\u00f8nes P et al (2024) The prevalence and rate of undiagnosed celiac disease in an adult general population, the Tr\u00f8ndelag Health Study, Norway. Clin Gastroenterol Hepatol. Available from: https:\/\/doi.org\/10.1016\/j.cgh.2024.06.027","DOI":"10.1016\/j.cgh.2024.06.027"},{"issue":"Suppl 1","key":"2778_CR12","first-page":"S3","volume":"56","author":"GK Makharia","year":"2022","unstructured":"Makharia GK, Chauhan A, Singh P, Ahuja V (2022) Review article: epidemiology of coeliac disease. Aliment Pharmacol Ther 56(Suppl 1):S3\u201317","journal-title":"Aliment Pharmacol Ther"},{"issue":"10","key":"2778_CR13","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1038\/ng.3643","volume":"48","author":"S McCarthy","year":"2016","unstructured":"McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood AR, Teumer A et al (2016) A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet 48(10):1279\u20131283","journal-title":"Nat Genet"},{"issue":"7","key":"2778_CR14","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1016\/S0753-3322(01)80003-2","volume":"54","author":"G Oberhuber","year":"2000","unstructured":"Oberhuber G (2000) Histopathology of celiac disease. Biomed Pharmacother 54(7):368\u2013372","journal-title":"Biomed Pharmacother"},{"issue":"11","key":"2778_CR15","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1038\/s41575-021-00510-9","volume":"18","author":"C Olano","year":"2021","unstructured":"Olano C (2021) A deep dive into the submerged \u2018coeliac iceberg\u2019. Nat Rev Gastroenterol Hepatol 18(11):748\u2013748","journal-title":"Nat Rev Gastroenterol Hepatol"},{"issue":"1","key":"2778_CR16","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1016\/j.ajhg.2021.11.008","volume":"109","author":"F Priv\u00e9","year":"2022","unstructured":"Priv\u00e9 F, Aschard H, Carmi S, Folkersen L, Hoggart C, O\u2019Reilly PF et al (2022) Portability of 245 polygenic scores when derived from the UK biobank and applied to 9 ancestry groups from the same cohort. Am J Hum Genet 109(1):12\u201323","journal-title":"Am J Hum Genet"},{"issue":"3","key":"2778_CR17","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","volume":"81","author":"S Purcell","year":"2007","unstructured":"Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D et al (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81(3):559\u2013575","journal-title":"Am J Hum Genet"},{"key":"2778_CR18","volume-title":"R: A Language and environment for statistical computing","author":"R Core Team","year":"2021","unstructured":"R Core Team (2021) R: A Language and environment for statistical computing. R Foundation for Statistical Computing, Vienna"},{"issue":"3","key":"2778_CR19","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/s41431-019-0520-4","volume":"28","author":"I Rica\u00f1o-Ponce","year":"2020","unstructured":"Rica\u00f1o-Ponce I, Gutierrez-Achury J, Costa AF, Deelen P, Kurilshikov A, Zorro MM et al (2020) Immunochip meta-analysis in European and Argentinian populations identifies two novel genetic loci associated with celiac disease. Eur J Hum Genet 28(3):313\u2013323","journal-title":"Eur J Hum Genet"},{"issue":"3","key":"2778_CR20","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1136\/gutjnl-2012-304110","volume":"63","author":"J Romanos","year":"2014","unstructured":"Romanos J, Ros\u00e9n A, Kumar V, Trynka G, Franke L, Szperl A et al (2014) Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants. Gut 63(3):415\u2013422","journal-title":"Gut"},{"key":"2778_CR21","volume-title":"RStudio: integrated development environment for R","author":"RStudio Team","year":"2020","unstructured":"RStudio Team (2020) RStudio: integrated development environment for R. RStudio, PBC., Boston"},{"issue":"11","key":"2778_CR22","doi-asserted-by":"publisher","first-page":"e1009049","DOI":"10.1371\/journal.pgen.1009049","volume":"16","author":"S Rubinacci","year":"2020","unstructured":"Rubinacci S, Delaneau O, Marchini J (2020) Genotype imputation using the positional burrows wheeler transform. PLoS Genet 16(11):e1009049","journal-title":"PLoS Genet"},{"issue":"7","key":"2778_CR23","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1038\/s41562-023-01579-9","volume":"7","author":"T Schoeler","year":"2023","unstructured":"Schoeler T, Speed D, Porcu E, Pirastu N, Pingault JB, Kutalik Z (2023) Participation bias in the UK biobank distorts genetic associations and downstream analyses. Nat Hum Behav 7(7):1216\u20131227","journal-title":"Nat Hum Behav"},{"issue":"6","key":"2778_CR24","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1016\/j.cgh.2017.06.037","volume":"16","author":"P Singh","year":"2018","unstructured":"Singh P, Arora A, Strand TA, Leffler DA, Catassi C, Green PH et al (2018) Global prevalence of Celiac disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol 16(6):823\u2013836e2","journal-title":"Clin Gastroenterol Hepatol"},{"issue":"8\u20139","key":"2778_CR25","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1007\/s00251-017-0985-7","volume":"69","author":"LM Sollid","year":"2017","unstructured":"Sollid LM (2017) The roles of MHC class II genes and post-translational modification in celiac disease. Immunogenetics 69(8\u20139):605\u2013616","journal-title":"Immunogenetics"},{"issue":"2","key":"2778_CR26","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1186\/s12864-016-2722-2","volume":"17","author":"G Stelzer","year":"2016","unstructured":"Stelzer G, Plaschkes I, Oz-Levi D, Alkelai A, Olender T, Zimmerman S et al (2016) VarElect: the phenotype-based variation prioritizer of the genecards suite. BMC Genomics 17(2):444","journal-title":"BMC Genomics"},{"issue":"12","key":"2778_CR27","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1038\/ng.998","volume":"43","author":"G Trynka","year":"2011","unstructured":"Trynka G, Hunt KA, Bockett NA, Romanos J, Mistry V, Szperl A et al (2011) Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet 43(12):1193\u20131201","journal-title":"Nat Genet"},{"issue":"7","key":"2778_CR28","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1038\/ng2058","volume":"39","author":"DA van Heel","year":"2007","unstructured":"van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye M et al (2007) A genome-wide association study for Celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 39(7):827\u2013829","journal-title":"Nat Genet"},{"issue":"16","key":"2778_CR29","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq603","volume":"38","author":"K Wang","year":"2010","unstructured":"Wang K, Li M, Hakonarson H (2010) ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 38(16):e164","journal-title":"Nucleic Acids Res"},{"issue":"9","key":"2778_CR30","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1038\/s41588-018-0184-y","volume":"50","author":"W Zhou","year":"2018","unstructured":"Zhou W, Nielsen JB, Fritsche LG, Dey R, Gabrielsen ME, Wolford BN et al (2018) Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nat Genet 50(9):1335\u20131341","journal-title":"Nat Genet"}],"container-title":["Human Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00439-025-02778-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00439-025-02778-2\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00439-025-02778-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,9]],"date-time":"2025-12-09T12:51:15Z","timestamp":1765284675000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00439-025-02778-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,29]]},"references-count":30,"journal-issue":{"issue":"11-12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["2778"],"URL":"https:\/\/doi.org\/10.1007\/s00439-025-02778-2","relation":{},"ISSN":["0340-6717","1432-1203"],"issn-type":[{"value":"0340-6717","type":"print"},{"value":"1432-1203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,29]]},"assertion":[{"value":"7 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 September 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"GeneCards\u2014\n                      \n                      . VarElect\u2014\n                      \n                      . PGS Catalog\u2014\n                      \n                      .","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Web resources"}}]}}