title: Ancestry-based stratified analysis of Immunochip data identifies novel associations with celiac disease.
abstract: To identify candidate genes in celiac disease (CD), we reanalyzed the whole Immunochip CD cohort using a different approach that clusters individuals based on immunoancestry prior to disease association analysis, rather than by geographical origin. We detected 636 new associated SNPs (P<7.02 × 10-07) and identified 5 novel genomic regions, extended 8 others previously identified and also detected 18 isolated signals defined by one or very few significant SNPs. To test whether we could identify putative candidate genes, we performed expression analyses of several genes from the top novel region (chr2:134533564-136169524), from a previously identified locus that is now extended, and a gene marked by an isolated SNP, in duodenum biopsies of active and treated CD patients, and non-celiac controls. In the largest novel region, CCNT2 and R3HDM1 were constitutively underexpressed in disease, even after gluten removal. Moreover, several genes within this region were coexpressed in patients, but not in controls. Other novel genes like KIF21B, REL and SORD also showed altered expression in active disease. Apart from the identification of novel CD loci, these results suggest that ancestry-based stratified analysis is an efficient strategy for association studies in complex diseases.
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV-EHU), BioCruces Health Research Institute, Leioa, Spain.
authors.forename: Koldo
authors.initials: K
authors.lastname: Garcia-Etxebarria
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV-EHU), BioCruces Health Research Institute, Leioa, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Jauregi-Miguel
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV-EHU), BioCruces Health Research Institute, Leioa, Spain.
authors.forename: Irati
authors.initials: I
authors.lastname: Romero-Garmendia
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV-EHU), BioCruces Health Research Institute, Leioa, Spain.
authors.forename: Leticia
authors.initials: L
authors.lastname: Plaza-Izurieta
authors.affiliation: Department of Pediatrics, Pediatric Gastroenterology Unit, Cruces University Hospital, University of the Basque Country (UPV-EHU), Barakaldo, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Legarda
authors.affiliation: Department of Pediatrics, Pediatric Gastroenterology Unit, Cruces University Hospital, University of the Basque Country (UPV-EHU), Barakaldo, Spain.
authors.forename: Iñaki
authors.initials: I
authors.lastname: Irastorza
authors.affiliation: Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV-EHU), BioCruces Health Research Institute, Leioa, Spain.
authors.forename: Jose Ramon
authors.identifier: 0000-0002-3176-501X
authors.initials: JR
authors.lastname: Bilbao
mesh_terms: D016022:Case-Control Studies; D002446:Celiac Disease / Q000235:genetics* / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism; D056426:Genetic Loci; D005983:Glutens / Q000378:metabolism; D006801:Humans; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: D005983:Glutens