title: Systematic annotation of celiac disease loci refines pathological pathways and suggests a genetic explanation for increased interferon-gamma levels.
abstract: Although genome-wide association studies and fine mapping have identified 39 non-HLA loci associated with celiac disease (CD), it is difficult to pinpoint the functional variants and susceptibility genes in these loci. We applied integrative approaches to annotate and prioritize functional single nucleotide polymorphisms (SNPs), genes and pathways affected in CD. CD-associated SNPs were intersected with regulatory elements categorized by the ENCODE project to prioritize functional variants, while results from cis-expression quantitative trait loci (eQTL) mapping in 1469 blood samples were combined with co-expression analyses to prioritize causative genes. To identify the key cell types involved in CD, we performed pathway analysis on RNA-sequencing data from different immune cell populations and on publicly available expression data on non-immune tissues. We discovered that CD SNPs are significantly enriched in B-cell-specific enhancer regions, suggesting that, besides T-cell processes, B-cell responses play a major role in CD. By combining eQTL and co-expression analyses, we prioritized 43 susceptibility genes in 36 loci. Pathway and tissue-specific expression analyses on these genes suggested enrichment of CD genes in the Th1, Th2 and Th17 pathways, but also predicted a role for four genes in the intestinal barrier function. We also discovered an intricate transcriptional connectivity between CD susceptibility genes and interferon-γ, a key effector in CD, despite the absence of CD-associated SNPs in the IFNG locus. Using systems biology, we prioritized the CD-associated functional SNPs and genes. By highlighting a role for B cells in CD, which classically has been described as a T-cell-driven disease, we offer new insights into the mechanisms and pathways underlying CD.
authors.affiliation: Department of Genetics s.withoff@umcg.nl v.kumar@umcg.nl vinodkmagadi@gmail.com.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Department of Genetics.
authors.forename: Javier
authors.initials: J
authors.lastname: Gutierrez-Achury
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku 20520, Finland and.
authors.forename: Kartiek
authors.initials: K
authors.lastname: Kanduri
authors.affiliation: Department of Genetics.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Almeida
authors.affiliation: Department of Genetics.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hrdlickova
authors.affiliation: Department of Genetics.
authors.forename: Daria V
authors.initials: DV
authors.lastname: Zhernakova
authors.affiliation: Department of Genetics.
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Westra
authors.affiliation: Department of Genetics.
authors.forename: Juha
authors.initials: J
authors.lastname: Karjalainen
authors.affiliation: Department of Genetics.
authors.forename: Isis
authors.initials: I
authors.lastname: Ricaño-Ponce
authors.affiliation: Department of Genetics.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Genetics.
authors.forename: Anna
authors.initials: A
authors.lastname: Stachurska
authors.affiliation: Department of Genetics.
authors.forename: Ettje F
authors.initials: EF
authors.lastname: Tigchelaar
authors.affiliation: Department of Rheumatology and Clinical Immunology and.
authors.forename: Wayel H
authors.initials: WH
authors.lastname: Abdulahad
authors.affiliation: Department of Information and Computer Science, Aalto University School of Science, Espoo 02150, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Lähdesmäki
authors.affiliation: Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.affiliation: Department of Genetics.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Zhernakova
authors.affiliation: Department of Genetics.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku 20520, Finland and.
authors.forename: Riitta
authors.initials: R
authors.lastname: Lahesmaa
authors.affiliation: Department of Genetics.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Genetics s.withoff@umcg.nl v.kumar@umcg.nl vinodkmagadi@gmail.com.
authors.forename: Sebo
authors.initials: S
authors.lastname: Withoff
mesh_terms: D002446:Celiac Disease / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D058977:Molecular Sequence Annotation; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
chemical_list: D007371:Interferon-gamma