{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T16:30:43Z","timestamp":1788107443251,"version":"build-2803163510"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T00:00:00Z","timestamp":1613088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:p>Beh\u00e7et's disease is a chronic multisystemic inflammatory disorder characterized by recurrent oral and genital ulcers. Although its etiology remains unclear, it is thought that both genetic and environmental factors contribute to the onset and progression of Beh\u00e7et's disease. Here, we provide an updated view of the genetic landscape and architecture of Beh\u00e7et's disease. Large-scale genetic studies performed to date revealed 21 genetic susceptibility loci associated with the disease at a GWAS level of significance (<jats:italic>p<\/jats:italic>-value = 5 \u00d7 10<jats:sup>\u22128<\/jats:sup>). We performed epigenetic pattern enrichment analysis in Beh\u00e7et's disease associated loci, providing new insights into the molecular mechanisms underlying its pathophysiology. Our data suggest the crucial involvement of several immune cell types, including natural killer cells, monocytes, and B cells in the pathogenesis of the disease. Pathway enrichment analysis identified important biological processes involved. Using large-scale genetic data available from ~200 immune-related loci (Immunochip), we estimate Beh\u00e7et's disease heritability to be at least 16%. We further used the same approach to estimate the heritability explained by the known Beh\u00e7et's disease-associated loci, suggesting that they explain ~ 60% of the genetic component underlying Beh\u00e7et's disease. These results indicate a significant role of non-genetic factors in causing Beh\u00e7et's disease and that additional genetic variation influencing the risk of Beh\u00e7et's disease remains to be identified. Finally, we calculated a cumulative genetic risk score across populations reinforcing the link between geographic variations in disease prevalence with its genetic component.<\/jats:p>","DOI":"10.3389\/fmed.2021.625710","type":"journal-article","created":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T19:52:19Z","timestamp":1613245939000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":36,"title":["Genetics of Beh\u00e7et's Disease: Functional Genetic Analysis and Estimating Disease Heritability"],"prefix":"10.3389","volume":"8","author":[{"given":"Lourdes","family":"Ortiz-Fern\u00e1ndez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amr H.","family":"Sawalha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,2,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"iii101","DOI":"10.1093\/rheumatology\/kez626","article-title":"Behcet: the syndrome","volume":"59","author":"Bettiol","year":"2020","journal-title":"Rheumatology (Oxford)."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2165","DOI":"10.1093\/rheumatology\/keq251","article-title":"Impact of Behcet's syndrome on health-related quality of life: influence of the type and number of symptoms","volume":"49","author":"Bernabe","year":"2010","journal-title":"Rheumatology (Oxford)."},{"key":"B3","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1136\/ard.43.6.783","article-title":"Influence of age of onset and patient's sex on the prevalence and severity of manifestations of Behcet's syndrome","volume":"43","author":"Yazici","year":"1984","journal-title":"Ann Rheum Dis."},{"key":"B4","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1034\/j.1399-0039.1999.540301.x","article-title":"Behcet's disease, the Silk Road and HLA-B51: historical and geographical perspectives","volume":"54","author":"Verity","year":"1999","journal-title":"Tissue Antigens."},{"key":"B5","doi-asserted-by":"publisher","first-page":"239","DOI":"10.5152\/eurjrheum.2017.17112","article-title":"Behcet's disease in the United States: a single center descriptive and comparative study","volume":"4","author":"Kilian","year":"2017","journal-title":"Eur J Rheumatol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1007\/s11739-018-2000-1","article-title":"Triggering agents and microbiome as environmental factors on Behcet's syndrome","volume":"14","author":"Mumcu","year":"2019","journal-title":"Intern Emerg Med."},{"key":"B7","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.clim.2016.06.002","article-title":"Sequencing of 16S rRNA reveals a distinct salivary microbiome signature in Behcet's disease","volume":"169","author":"Coit","year":"2016","journal-title":"Clin Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1093\/rheumatology\/keh236","article-title":"Oral health is impaired in Behcet's disease and is associated with disease severity","volume":"43","author":"Mumcu","year":"2004","journal-title":"Rheumatology."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1016\/S0140-6736(73)93343-6","article-title":"Letter: HL-A5 and Behcet's disease","volume":"2","author":"Ohno","year":"1973","journal-title":"Lancet."},{"key":"B10","first-page":"164","article-title":"The candidate gene approach","volume":"24","author":"Kwon","year":"2000","journal-title":"Alcohol Res Health."},{"key":"B11","doi-asserted-by":"publisher","first-page":"D1005","DOI":"10.1093\/nar\/gky1120","article-title":"The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics 2019","volume":"47","author":"Buniello","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"R66","DOI":"10.1186\/ar2695","article-title":"Identification of novel genetic susceptibility loci for Behcet's disease using a genome-wide association study","volume":"11","author":"Fei","year":"2009","journal-title":"Arthritis Res Ther."},{"key":"B13","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1038\/ng.624","article-title":"Genome-wide association studies identify IL23R-IL12RB2 and IL10 as Behcet's disease susceptibility loci","volume":"42","author":"Mizuki","year":"2010","journal-title":"Nat Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1038\/ng.625","article-title":"Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease","volume":"42","author":"Remmers","year":"2010","journal-title":"Nat Genet."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1510","DOI":"10.1136\/annrheumdis-2011-200288","article-title":"Genome-wide association study identifies GIMAP as a novel susceptibility locus for Behcet's disease","volume":"72","author":"Lee","year":"2013","journal-title":"Ann Rheum Dis."},{"key":"B16","doi-asserted-by":"publisher","first-page":"4104","DOI":"10.1002\/art.37708","article-title":"Identification of a susceptibility locus in STAT4 for Behcet's disease in Han Chinese in a genome-wide association study","volume":"64","author":"Hou","year":"2012","journal-title":"Arthritis Rheum."},{"key":"B17","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/ng.2520","article-title":"Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B*51 and ERAP1","volume":"45","author":"Kirino","year":"2013","journal-title":"Nat Genet."},{"key":"B18","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1038\/ng.2551","article-title":"Identification of multiple independent susceptibility loci in the HLA region in Behcet's disease","volume":"45","author":"Hughes","year":"2013","journal-title":"Nat Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"8867","DOI":"10.1073\/pnas.1406575111","article-title":"Behcet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity","volume":"111","author":"Ombrello","year":"2014","journal-title":"Proc Natl Acad Sci USA."},{"key":"B20","doi-asserted-by":"publisher","first-page":"618","DOI":"10.1136\/annrheumdis-2013-204475","article-title":"FUT2: filling the gap between genes and environment in Behcet's disease?","volume":"74","author":"Xavier","year":"2015","journal-title":"Ann Rheum Dis."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e0119085","DOI":"10.1371\/journal.pone.0119085","article-title":"Genome-wide association study in an admixed case series reveals IL12A as a new candidate in Behcet disease","volume":"10","author":"Kappen","year":"2015","journal-title":"PLoS ONE."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e0161305","DOI":"10.1371\/journal.pone.0161305","article-title":"Genetic analysis with the immunochip platform in behcet disease. Identification of residues associated in the HLA class i region and new susceptibility loci","volume":"11","author":"Ortiz-Fernandez","year":"2016","journal-title":"PLoS ONE."},{"key":"B23","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1038\/ng.3786","article-title":"Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behcet's disease susceptibility","volume":"49","author":"Takeuchi","year":"2017","journal-title":"Nat Genet."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/art.41637","article-title":"Genetic association of a gain of function interferon gamma receptor 1 (IFNGR1) polymorphism and the intergenic region LNCAROD\/DKK1 with Beh\u00e7et's disease","author":"Ortiz Fern\u00e1ndez","year":"2021","journal-title":"Arthritis Rheumatol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1136\/ard.2009.108571","article-title":"Genetics of Behcet disease inside and outside the MHC","volume":"69","author":"Meguro","year":"2010","journal-title":"Ann Rheum Dis."},{"key":"B26","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1007\/s00251-015-0841-6","article-title":"On the genetics of the Silk Route: association analysis of HLA, IL10, and IL23R-IL12RB2 regions with Behcet's disease in an Iranian population","volume":"67","author":"Carapito","year":"2015","journal-title":"Immunogenetics."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2761","DOI":"10.1002\/art.34437","article-title":"Association study of IL10 and IL23R-IL12RB2 in Iranian patients with Behcet's disease","volume":"64","author":"Xavier","year":"2012","journal-title":"Arthritis Rheum."},{"key":"B28","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1136\/ard.2009.119420","article-title":"IL-23R gene confers susceptibility to Behcet's disease in a Chinese Han population","volume":"69","author":"Jiang","year":"2010","journal-title":"Ann Rheum Dis."},{"key":"B29","doi-asserted-by":"publisher","first-page":"740","DOI":"10.1016\/j.lfs.2012.03.017","article-title":"Interactions between IL17A, IL23R, and STAT4 polymorphisms confer susceptibility to intestinal Behcet's disease in Korean population","volume":"90","author":"Kim","year":"2012","journal-title":"Life Sci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1111\/ced.12400","article-title":"Association of interleukin-23 receptor gene polymorphism with Behcet disease","volume":"39","author":"Yalcin","year":"2014","journal-title":"Clin Exp Dermatol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"2742","DOI":"10.1002\/art.39240","article-title":"Brief report: association of CCR1, KLRC4, IL12A-AS1, STAT4, and ERAP1 with Behcet's disease in Iranians","volume":"67","author":"Sousa","year":"2015","journal-title":"Arthritis Rheumatol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.humimm.2013.11.009","article-title":"IL10 polymorphisms associated with Behcet's disease in Chinese Han","volume":"75","author":"Wu","year":"2014","journal-title":"Hum Immunol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1186\/ar3204","article-title":"Promise and pitfalls of the immunochip","volume":"13","author":"Cortes","year":"2011","journal-title":"Arthritis Res Ther."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1496","DOI":"10.4049\/jimmunol.1701061","article-title":"Novel transcriptional activity and extensive allelic imbalance in the human MHC region","volume":"200","author":"Gensterblum-Miller","year":"2018","journal-title":"J Immunol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1186\/s13075-015-0585-6","article-title":"Characterization of the major histocompatibility complex locus association with Behcet's disease in Iran","volume":"17","author":"Xavier","year":"2015","journal-title":"Arthritis Res Ther."},{"key":"B36","doi-asserted-by":"publisher","first-page":"424","DOI":"10.3389\/fgene.2020.00424","article-title":"From GWAS to function: using functional genomics to identify the mechanisms underlying complex diseases","volume":"11","author":"Cano-Gamez","year":"2020","journal-title":"Front Genet."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2256","DOI":"10.1093\/bioinformatics\/btw169","article-title":"GenomeRunner web server: regulatory similarity and differences define the functional impact of SNP sets","volume":"32","author":"Dozmorov","year":"2016","journal-title":"Bioinformatics."},{"key":"B38","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1038\/nature14248","article-title":"Integrative analysis of 111 reference human epigenomes","volume":"518","author":"Roadmap Epigenomics","year":"2015","journal-title":"Nature."},{"key":"B39","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1038\/nature11247","article-title":"An integrated encyclopedia of DNA elements in the human genome","volume":"489","author":"Consortium","year":"2012","journal-title":"Nature."},{"key":"B40","first-page":"6","article-title":"Behcet's disease: an update on the pathogenesis","volume":"19","author":"Gul","year":"2001","journal-title":"Clin Exp Rheumatol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"1206","DOI":"10.1016\/j.intimp.2013.07.017","article-title":"Possible mechanisms of neutrophil activation in Behcet's disease","volume":"17","author":"Neves","year":"2013","journal-title":"Int Immunopharmacol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1126\/science.1262110","article-title":"Human genomics. The genotype-tissue expression (GTEx) pilot analysis: multitissue gene regulation in humans","volume":"348","author":"Consortium","year":"2015","journal-title":"Science."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2511","DOI":"10.1093\/bioinformatics\/btw173","article-title":"CHiCP: a web-based tool for the integrative and interactive visualization of promoter capture Hi-C datasets","volume":"32","author":"Schofield","year":"2016","journal-title":"Bioinformatics."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape provides a biologist-oriented resource for the analysis of systems-level datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat Commun."},{"key":"B45","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s12969-017-0162-4","article-title":"Intestinal Behcet and Crohn's disease: two sides of the same coin","volume":"15","author":"Valenti","year":"2017","journal-title":"Pediatr Rheumatol Online J."},{"key":"B46","first-page":"488","article-title":"Epidemiology of Adamantiades-Behcet's disease","volume":"150","author":"Zouboulis","year":"1999","journal-title":"Ann Med Interne."},{"key":"B47","doi-asserted-by":"publisher","first-page":"411","DOI":"10.3349\/ymj.1997.38.6.411","article-title":"Epidemiological features of Adamantiades-Behcet's disease in Germany and in Europe","volume":"38","author":"Zouboulis","year":"1997","journal-title":"Yonsei Med J."},{"key":"B48","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1007\/BF02932268","article-title":"A study of comparison between the nationwide epidemiological survey in 1991 and previous surveys on behcet's disease in Japan","volume":"4","author":"Nishiyama","year":"1999","journal-title":"Environ Health Prev Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/S0022-3476(99)70333-1","article-title":"Familial aggregation in Behcet's disease: high frequency in siblings and parents of pediatric probands","volume":"135","author":"Kone-Paut","year":"1999","journal-title":"J Pediatr."},{"key":"B50","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1136\/ard.59.8.622","article-title":"Familial aggregation of Behcet's disease in Turkey","volume":"59","author":"Gul","year":"2000","journal-title":"Ann Rheum Dis."},{"key":"B51","first-page":"S62","article-title":"A twin study in Behcet's syndrome","volume":"28","author":"Masatlioglu","year":"2010","journal-title":"Clin Exp Rheumatol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1038\/nrg2322","article-title":"Heritability in the genomics era\u2013concepts and misconceptions","volume":"9","author":"Visscher","year":"2008","journal-title":"Nat Rev Genet."},{"key":"B53","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1038\/s41588-018-0108-x","article-title":"Comparison of methods that use whole genome data to estimate the heritability and genetic architecture of complex traits","volume":"50","author":"Evans","year":"2018","journal-title":"Nat Genet."},{"key":"B54","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.ajhg.2010.11.011","article-title":"GCTA: a Tool for genome-wide complex trait analysis","volume":"88","author":"Yang","year":"2011","journal-title":"Am J Hum Genet."},{"key":"B55","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1038\/ng.3390","article-title":"Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index","volume":"47","author":"Yang","year":"2015","journal-title":"Nat Genet."},{"key":"B56","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1038\/ng.3941","article-title":"Concepts, estimation and interpretation of SNP-based heritability","volume":"49","author":"Yang","year":"2017","journal-title":"Nat Genet."},{"key":"B57","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1046\/j.1365-4362.2003.01893.x","article-title":"Prevalence of Behcet's disease in Istanbul, Turkey","volume":"42","author":"Azizlerli","year":"2003","journal-title":"Int J Dermatol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"e1004269","DOI":"10.1371\/journal.pgen.1004269","article-title":"Statistical power to detect genetic (co)variance of complex traits using SNP data in unrelated samples","volume":"10","author":"Visscher","year":"2014","journal-title":"PLoS Genet."},{"key":"B59","doi-asserted-by":"publisher","first-page":"e1003993","DOI":"10.1371\/journal.pgen.1003993","article-title":"Quantifying missing heritability at known GWAS loci","volume":"9","author":"Gusev","year":"2013","journal-title":"PLoS Genet."},{"key":"B60","doi-asserted-by":"publisher","first-page":"694","DOI":"10.1136\/annrheumdis-2011-200385","article-title":"Analysis of autosomal genes reveals gene-sex interactions and higher total genetic risk in men with systemic lupus erythematosus","volume":"71","author":"Hughes","year":"2012","journal-title":"Ann Rheum Dis."},{"key":"B61","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1038\/nature15393","article-title":"A global reference for human genetic variation","volume":"526","author":"Auton","year":"2015","journal-title":"Nature."},{"key":"B62","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/s41576-019-0127-1","article-title":"Benefits and limitations of genome-wide association studies","volume":"20","author":"Tam","year":"2019","journal-title":"Nat Rev Genet."},{"key":"B63","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1038\/s41588-020-0580-y","article-title":"The GWAS Diversity Monitor tracks diversity by disease in real time","volume":"52","author":"Mills","year":"2020","journal-title":"Nat Genet."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.625710\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,2,13]],"date-time":"2021-02-13T19:52:27Z","timestamp":1613245947000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2021.625710\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,12]]},"references-count":63,"alternative-id":["10.3389\/fmed.2021.625710"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2021.625710","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,12]]},"article-number":"625710"}}