Association of the TSHR gene with Graves' disease: the first disease specific locus.
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.
Dechairo
Bryan M
BM
Target Discovery, Oxagen Ltd., Abingdon OX14 4RY, UK.
Zabaneh
Delilah
D
Collins
Joanne
J
Brand
Oliver
O
Dawson
Gary J
GJ
Green
Angie P
AP
Mackay
Ian
I
Franklyn
Jayne A
JA
Connell
John M
JM
Wass
John A H
JA
Wiersinga
Wilmar M
WM
Hegedus
Laszlo
L
Brix
Thomas
T
Robinson
Bruce G
BG
Hunt
Penny J
PJ
Weetman
Anthony P
AP
Carey
Alisoun H
AH
Gough
Stephen C
SC
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
D011989:Receptors, Thyrotropin