title: Genome-wide association analysis of autoantibody positivity in type 1 diabetes cases.
abstract: The genetic basis of autoantibody production is largely unknown outside of associations located in the major histocompatibility complex (MHC) human leukocyte antigen (HLA) region. The aim of this study is the discovery of new genetic associations with autoantibody positivity using genome-wide association scan single nucleotide polymorphism (SNP) data in type 1 diabetes (T1D) patients with autoantibody measurements. We measured two anti-islet autoantibodies, glutamate decarboxylase (GADA, n = 2,506), insulinoma-associated antigen 2 (IA-2A, n = 2,498), antibodies to the autoimmune thyroid (Graves') disease (AITD) autoantigen thyroid peroxidase (TPOA, n = 8,300), and antibodies against gastric parietal cells (PCA, n = 4,328) that are associated with autoimmune gastritis. Two loci passed a stringent genome-wide significance level (p<10(-10)): 1q23/FCRL3 with IA-2A and 9q34/ABO with PCA. Eleven of 52 non-MHC T1D loci showed evidence of association with at least one autoantibody at a false discovery rate of 16%: 16p11/IL27-IA-2A, 2q24/IFIH1-IA-2A and PCA, 2q32/STAT4-TPOA, 10p15/IL2RA-GADA, 6q15/BACH2-TPOA, 21q22/UBASH3A-TPOA, 1p13/PTPN22-TPOA, 2q33/CTLA4-TPOA, 4q27/IL2/TPOA, 15q14/RASGRP1/TPOA, and 12q24/SH2B3-GADA and TPOA. Analysis of the TPOA-associated loci in 2,477 cases with Graves' disease identified two new AITD loci (BACH2 and UBASH3A).
authors.affiliation: Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, National Institute for Health Research Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom. v.plagnol@ucl.ac.uk
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: Joanna M M
authors.initials: JM
authors.lastname: Howson
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Smyth
authors.forename: Neil
authors.initials: N
authors.lastname: Walker
authors.forename: Jason P
authors.initials: JP
authors.lastname: Hafler
authors.forename: Chris
authors.initials: C
authors.lastname: Wallace
authors.forename: Helen
authors.initials: H
authors.lastname: Stevens
authors.forename: Laura
authors.initials: L
authors.lastname: Jackson
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Simmonds
authors.forename: Polly J
authors.initials: PJ
authors.lastname: Bingley
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Gough
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
mesh_terms: D000017:ABO Blood-Group System / Q000235:genetics; D000293:Adolescent; D001323:Autoantibodies / Q000235:genetics* / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D055106:Genome-Wide Association Study; D006111:Graves Disease / Q000235:genetics / Q000276:immunology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics
chemical_list: D000017:ABO Blood-Group System; D001323:Autoantibodies; C551993:FCRL1 protein, human; C457775:FCRL3 protein, human; D008565:Membrane Proteins; D011971:Receptors, Immunologic