title: Genetic risk variants for autoimmune diseases that influence gene expression in thymus.
abstract: Genome-wide association studies (GWAS) have boosted our knowledge of genetic risk variants in autoimmune diseases (AIDs). Most risk variants are located within or near genes with immunological functions, and the majority is found to be non-coding, pointing towards a regulatory role. In this study, we performed a cis expression quantitative trait locus (eQTL) screen restricted to 353 AID associated risk variants selected from the GWAS catalog to investigate whether these single nucleotide polymorphisms (SNPs) influence gene expression in thymus. Genotypes were obtained by Immunochip (Ichip) and tested against expression of surrounding genes (±1 Mb) in human thymic tissue (n = 42). We identified eight significant eQTLs located within seven genetic regions (FCRL3, RNASET2, C2orf74, NPIPB8, SIRPG, SYS1 and AJ006998.2) where the expression was associated with AID risk SNPs at a study-wide level of significance (P < 2.7 × 10-5). In NPIPB8 and AJ006998.2, the eQTL signals appeared to be thymus-specific. Furthermore, many AID risk SNPs from GWAS have been subsequently fine-mapped in recent Ichip projects, and fine-mapped AID SNPs overlapped with the thymic eQTLs within RNASET2 and SIRPG Finally, in all the eQTL regions, except C2orf74, SNPs underlying the thymic eQTLs were predicted to interfere with transcription factors important in T cell development. Our study therefore reveals autoimmune risk variants that act as eQTLs in thymus, and suggest that thymic gene regulation may play a functional role at some AID risk loci.
authors.affiliation: Department of Medical Genetics, Oslo University Hospital ingvild.gabrielsen@medisin.uio.no.|K. G. Jebsen Inflammation Research Centre.
authors.forename: Ingvild S M
authors.initials: IS
authors.lastname: Gabrielsen
authors.affiliation: Department of Medical Genetics, Oslo University Hospital.
authors.forename: Silja Svanstrøm
authors.initials: SS
authors.lastname: Amundsen
authors.affiliation: Department of Medical Genetics, Oslo University Hospital.|K. G. Jebsen Inflammation Research Centre.
authors.forename: Hanna
authors.initials: H
authors.lastname: Helgeland
authors.affiliation: Department of Medical Genetics, Oslo University Hospital.|K. G. Jebsen Inflammation Research Centre.
authors.forename: Siri Tennebø
authors.initials: ST
authors.lastname: Flåm
authors.affiliation: Department of Medical Genetics, Oslo University Hospital.|Faculty of Health Sciences, Oslo University College, 0130 Oslo, Norway.
authors.forename: Nimo
authors.initials: N
authors.lastname: Hatinoor
authors.affiliation: Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation.
authors.forename: Kristian
authors.initials: K
authors.lastname: Holm
authors.affiliation: Department of Medical Genetics, Oslo University Hospital.|Department of Immunology, Oslo University Hospital, University of Oslo, 0424 Oslo, Norway and.
authors.forename: Marte K
authors.initials: MK
authors.lastname: Viken
authors.affiliation: Department of Medical Genetics, Oslo University Hospital.|K. G. Jebsen Inflammation Research Centre.
authors.forename: Benedicte A
authors.initials: BA
authors.lastname: Lie
mesh_terms: D001327:Autoimmune Diseases / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D012307:Risk Factors; D013950:Thymus Gland / Q000378:metabolism*