title: Systematic Evaluation of Genes and Genetic Variants Associated with Type 1 Diabetes Susceptibility.
abstract: Genome-wide association studies have found >60 loci that confer genetic susceptibility to type 1 diabetes (T1D). Many of these are defined only by anonymous single nucleotide polymorphisms: the underlying causative genes, as well as the molecular bases by which they mediate susceptibility, are not known. Identification of how these variants affect the complex mechanisms contributing to the loss of tolerance is a challenge. In this study, we performed systematic analyses to characterize these variants. First, all known genes in strong linkage disequilibrium (r(2) > 0.8) with the reported single nucleotide polymorphisms for each locus were tested for commonly occurring nonsynonymous variations. We found only a total of 22 candidate genes at 16 T1D loci with common nonsynonymous alleles. Next, we performed functional studies to examine the effect of non-HLA T1D risk alleles on regulating expression levels of genes in four different cell types: EBV-transformed B cell lines (resting and 6 h PMA stimulated) and purified CD4(+) and CD8(+) T cells. We mapped cis-acting expression quantitative trait loci and found 24 non-HLA loci that affected the expression of 31 transcripts significantly in at least one cell type. Additionally, we observed 25 loci that affected 38 transcripts in trans. In summary, our systems genetics analyses defined the effect of T1D risk alleles on levels of gene expression and provide novel insights into the complex genetics of T1D, suggesting that most of the T1D risk alleles mediate their effect by influencing expression of multiple nearby genes.
authors.affiliation: Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Nedlands, Western Australia 6009, Australia; Centre of Medical Research, University of Western Australia, Nedlands, Western Australia 6009, Australia;
authors.forename: Ramesh
authors.identifier: http://orcid.org/0000-0002-4827-4778
authors.initials: R
authors.lastname: Ram
authors.affiliation: Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Nedlands, Western Australia 6009, Australia; Centre of Medical Research, University of Western Australia, Nedlands, Western Australia 6009, Australia;
authors.forename: Munish
authors.identifier: http://orcid.org/0000-0003-1955-6976
authors.initials: M
authors.lastname: Mehta
authors.affiliation: Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Nedlands, Western Australia 6009, Australia; Centre of Medical Research, University of Western Australia, Nedlands, Western Australia 6009, Australia;
authors.forename: Quang T
authors.initials: QT
authors.lastname: Nguyen
authors.affiliation: Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Nedlands, Western Australia 6009, Australia; Centre of Medical Research, University of Western Australia, Nedlands, Western Australia 6009, Australia;
authors.forename: Irma
authors.identifier: http://orcid.org/0000-0003-2177-0488
authors.initials: I
authors.lastname: Larma
authors.affiliation: Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore 636921; Ulm University Medical Centre, Department of Internal Medicine I, Ulm University, 89081 Ulm, Germany;
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Boehm
authors.affiliation: Department of Pediatrics, Herlev and Gentofte Hospital, 2730 Herlev, Denmark;
authors.forename: Flemming
authors.identifier: http://orcid.org/0000-0003-3274-5448
authors.initials: F
authors.lastname: Pociot
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL 32610; and Genetics Institute, University of Florida, Gainesville, FL 32610.
authors.forename: Patrick
authors.initials: P
authors.lastname: Concannon
authors.affiliation: Centre for Diabetes Research, Harry Perkins Institute of Medical Research, Nedlands, Western Australia 6009, Australia; Centre of Medical Research, University of Western Australia, Nedlands, Western Australia 6009, Australia; grant.morahan@uwa.edu.au.
authors.forename: Grant
authors.identifier: http://orcid.org/0000-0002-8562-7325
authors.initials: G
authors.lastname: Morahan
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002461:Cell Line, Transformed; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D004843:Epistasis, Genetic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D015203:Reproducibility of Results