Abstract
BackgroundGraves’ disease is an autoimmune thyroid disease of complex inheritance. Multiple genetic susceptibility loci are thought to be involved in Graves’ disease and it is therefore likely that these can be identified by genome wide association studies. This study aimed to determine if a genome wide association study, using a pooling methodology, could detect genomic loci associated with Graves’ disease.ResultsNineteen of the top ranking single nucleotide polymorphisms including HLA-DQA1 and C6orf10, were clustered within the Major Histo-compatibility Complex region on chromosome 6p21, with rs1613056 reaching genome wide significance (p = 5 × 10−8). Technical validation of top ranking non-Major Histo-compatablity complex single nucleotide polymorphisms with individual genotyping in the discovery cohort revealed four single nucleotide polymorphisms with p ≤ 10−4. Rs17676303 on chromosome 1q23.1, located upstream of FCRL3, showed evidence of association with Graves’ disease across the discovery, replication and combined cohorts. A second single nucleotide polymorphism rs9644119 downstream of DPYSL2 showed some evidence of association supported by finding in the replication cohort that warrants further study.ConclusionsPooled genome wide association study identified a genetic variant upstream of FCRL3 as a susceptibility locus for Graves’ disease in addition to those identified in the Major Histo-compatibility Complex. A second locus downstream of DPYSL2 is potentially a novel genetic variant in Graves’ disease that requires further confirmation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3276-z) contains supplementary material, which is available to authorized users.
Highlights
Graves’ disease is an autoimmune thyroid disease of complex inheritance
Discovery cohort The Australian Thyroid-associated Orbitopathy Research (ATOR) discovery cohort consisting of 412 Graves’ disease (GD) cases with and without Graves’ orbitopathy of European descent was recruited from endocrinology and ophthalmology clinics in the hospitals and private practices from Victoria and South Australia
In the discovery Genome wide association studies (GWAS), 19 of the top 30 ranking Single nucleotide polymorphism (SNP) clustered within the major histo-compatability complex (MHC) region on chromosome 6p21 including rs9272937 in Human leukocyte antigen (HLA)-DQA1 (p 10−7), two SNPs within C6orf10 (p 10−7), and rs1613056 reaching genome wide significance (p = 5 × 10−8) (Additional file 1: Table S1)
Summary
Graves’ disease is an autoimmune thyroid disease of complex inheritance. Multiple genetic susceptibility loci are thought to be involved in Graves’ disease and it is likely that these can be identified by genome wide association studies. GD is a complex disease with a strong familial predisposition; [3,4,5,6,7] the triggers are poorly understood but various environmental factors were linked to onset of GD such as stress, smoking and Yersinia infection in genetically susceptible individuals [8, 9]. The concordance rate for GD in monozygotic twins is significantly higher than dizygotic twins and model-fitting analysis predicted that genetic factors account for 79 % of disease heritability in
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