title: Association of the TSHR gene with Graves' disease: the first disease specific locus.
abstract: The development of autoimmune thyroid disease (AITD) is associated with autoantibodies directed against the thyroid stimulating hormone receptor (TSHR). Previous studies have failed to demonstrate a consistent association between the TSHR and AITD, or any of its sub-phenotypes. In the present study, we analysed the linkage disequilibrium (LD) structure encompassing the TSHR, to identify LD 'blocks' and SNPs, which capture the majority of intra-block haplotype diversity. The haplotype tagging SNPs, plus all common SNPs reported in previous studies were genotyped in 1,059 AITD Caucasian cases and 971 Caucasian controls. A haplotype, across two LD blocks, showed association (P<1 x 10(-6), OR 1.7) with Graves' disease (GD) but not autoimmune hypothyroidism (AIH). We replicated these findings by genotyping the most associated GD SNP, rs2268458, in a separate UK Caucasian cohort of 1,366 AITD cases and 1,061 controls (GD, P=2 x 10(-6), OR 1.3; AIH, P=NS). These results in two independent Caucasian data sets suggest that the TSHR is the first replicated GD-specific locus meriting further fine mapping and functional analysis to identify the aetiological variants.
authors.affiliation: Target Discovery, Oxagen Ltd., Abingdon OX14 4RY, UK.
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Dechairo
authors.forename: Delilah
authors.initials: D
authors.lastname: Zabaneh
authors.forename: Joanne
authors.initials: J
authors.lastname: Collins
authors.forename: Oliver
authors.initials: O
authors.lastname: Brand
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Dawson
authors.forename: Angie P
authors.initials: AP
authors.lastname: Green
authors.forename: Ian
authors.initials: I
authors.lastname: Mackay
authors.forename: Jayne A
authors.initials: JA
authors.lastname: Franklyn
authors.forename: John M
authors.initials: JM
authors.lastname: Connell
authors.forename: John A H
authors.initials: JA
authors.lastname: Wass
authors.forename: Wilmar M
authors.initials: WM
authors.lastname: Wiersinga
authors.forename: Laszlo
authors.initials: L
authors.lastname: Hegedus
authors.forename: Thomas
authors.initials: T
authors.lastname: Brix
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Robinson
authors.forename: Penny J
authors.initials: PJ
authors.lastname: Hunt
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Weetman
authors.forename: Alisoun H
authors.initials: AH
authors.lastname: Carey
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Gough
mesh_terms: D016022:Case-Control Studies; D002874:Chromosome Mapping; D005828:Genetics, Population; D006111:Graves Disease / Q000453:epidemiology / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011989:Receptors, Thyrotropin / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology; D044465:White People / Q000235:genetics
chemical_list: D011989:Receptors, Thyrotropin