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      Seven newly identified loci for autoimmune thyroid disease

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          Abstract

          Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), is one of the most common of the immune-mediated diseases. To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism (SNP) array, the ImmunoChip. The SNP array contains all known and genotype-able SNPs across 186 distinct susceptibility loci associated with one or more immune-mediated diseases. After stringent quality control, we analysed 103 875 common SNPs (minor allele frequency >0.05) in 2285 GD and 462 HT patients and 9364 controls. We found evidence for seven new AITD risk loci ( P < 1.12 × 10 −6; a permutation test derived significance threshold), five at locations previously associated and two at locations awaiting confirmation, with other immune-mediated diseases.

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          Assessing the impact of population stratification on genetic association studies.

          Matthew Freedman, David Reich, Kathryn Penney … (2004)
          Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and case-cohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies.
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            Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease.

            Kristien Boelaert, Paul Newby, Matthew J. Simmonds … (2010)
            Common autoimmune disorders tend to coexist in the same subjects and to cluster in families. We performed a cross-sectional multicenter study of 3286 Caucasian subjects (2791 with Graves' disease; 495 with Hashimoto's thyroiditis) attending UK hospital thyroid clinics to quantify the prevalence of coexisting autoimmune disorders. All subjects completed a structured questionnaire seeking a personal and parental history of common autoimmune disorders, as well as a history of hyperthyroidism or hypothyroidism among parents. The frequency of another autoimmune disorder was 9.67% in Graves' disease and 14.3% in Hashimoto's thyroiditis index cases (P=.005). Rheumatoid arthritis was the most common coexisting autoimmune disorder (found in 3.15% of Graves' disease and 4.24% of Hashimoto's thyroiditis cases). Relative risks of almost all other autoimmune diseases in Graves' disease or Hashimoto's thyroiditis were significantly increased (>10 for pernicious anemia, systemic lupus erythematosus, Addison's disease, celiac disease, and vitiligo). There was relative "clustering" of Graves' disease in the index case with parental hyperthyroidism and of Hashimoto's thyroiditis in the index case with parental hypothyroidism. Relative risks for most other coexisting autoimmune disorders were markedly increased among parents of index cases. This is one of the largest studies to date to quantify the risk of diagnosis of coexisting autoimmune diseases in more than 3000 index cases with well-characterized Graves' disease or Hashimoto's thyroiditis. These risks highlight the importance of screening for other autoimmune diagnoses if subjects with autoimmune thyroid disease present with new or nonspecific symptoms. Copyright (c) 2010 Elsevier Inc. All rights reserved.
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              A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk.

              Glenda Gray, S. Langley, Y. Li … (2010)
              Combined analyses of gene networks and DNA sequence variation can provide new insights into the aetiology of common diseases that may not be apparent from genome-wide association studies alone. Recent advances in rat genomics are facilitating systems-genetics approaches. Here we report the use of integrated genome-wide approaches across seven rat tissues to identify gene networks and the loci underlying their regulation. We defined an interferon regulatory factor 7 (IRF7)-driven inflammatory network (IDIN) enriched for viral response genes, which represents a molecular biomarker for macrophages and which was regulated in multiple tissues by a locus on rat chromosome 15q25. We show that Epstein-Barr virus induced gene 2 (Ebi2, also known as Gpr183), which lies at this locus and controls B lymphocyte migration, is expressed in macrophages and regulates the IDIN. The human orthologous locus on chromosome 13q32 controlled the human equivalent of the IDIN, which was conserved in monocytes. IDIN genes were more likely to associate with susceptibility to type 1 diabetes (T1D)-a macrophage-associated autoimmune disease-than randomly selected immune response genes (P = 8.85 × 10(-6)). The human locus controlling the IDIN was associated with the risk of T1D at single nucleotide polymorphism rs9585056 (P = 7.0 × 10(-10); odds ratio, 1.15), which was one of five single nucleotide polymorphisms in this region associated with EBI2 (GPR183) expression. These data implicate IRF7 network genes and their regulatory locus in the pathogenesis of T1D.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Hum Mol Genet
                Journal ID (iso-abbrev): Hum. Mol. Genet
                Journal ID (publisher-id): hmg
                Journal ID (hwp): hmg
                Title: Human Molecular Genetics
                Publisher: Oxford University Press
                ISSN (Print): 0964-6906
                ISSN (Electronic): 1460-2083
                Publication date (Print): 1 December 2012
                Publication date (Electronic): 24 August 2012
                Publication date PMC-release: 24 August 2012
                Volume: 21
                Issue: 23
                Pages: 5202-5208
                Affiliations
                [1 ]Department of Medical Genetics, Cambridge Institute for Medical Research, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, NIHR Cambridge Biomedical Research Centre, University of Cambridge, Addenbrooke's Hospital , Cambridge,
                [2 ]Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital , Oxford,
                [3 ]School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham , Birmingham, and
                [4 ]NIHR Oxford Biomedical Research Centre, Churchill Hospital , Oxford, UK
                Author notes
                [* ]To whom correspondence should be addressed. Tel: +44 1223762107; Fax: +44 1223762102; Email jason.cooper@ 123456cimr.cam.ac.uk
                [†]

                Joint first authors.

                [‡]

                A full list of the Wellcome Trust Case Control Consortium investigators involved in this study are included in the Supplementary Information.

                [¶]

                Joint senior authors.

                [¶]

                Joint senior authors.

                Article
                Publisher ID: dds357
                DOI: 10.1093/hmg/dds357
                PMC ID: 3490518
                PubMed ID: 22922229
                SO-VID: b5b8f94a-08ac-4150-8593-430260dbc7ae
                Copyright © © The Author 2012. Published by Oxford University Press.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 31 May 2012
                Date revision received : 6 August 2012
                Date accepted : 20 August 2012
                Categories
                Subject: Association Studies Articles

                ScienceOpen disciplines: Genetics
                Data availability:
                ScienceOpen disciplines: Genetics

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