Evidence for a Graves' disease susceptibility locus at chromosome Xp11 in a United Kingdom population

Graves' disease (GD), which has a strong female preponderance (female/male ratio, >5:1), is inherited as a complex genetic trait. Loci for GD have sta rted to be defined using genome-wide approaches for genetic linkage. To dat e, 3 loci have been confirmed in at least 2 cohorts of GD patients, the str ongest effect being at the cytotoxic T lymphocyte antigen-4 (CTLA-4) locus on chromosome 2q33 in our population. Two other loci for GD have recently b een proposed, but not confirmed, on chromosomes Xq21(GD3) and 14q31(GD1). W e studied a cohort of 75 sibling pairs with GD from the United Kingdom for linkage to 12 markers over a 83-cM region of the X chromosome and for 8 mar kers over a 36-cM region of 14q31-q33. A peak multipoint nonparametric link age score of 2.21 (P = 0.014) was found at marker DXS8083 on Xp11, which in creased to a nonparametric linkage score of 3.18 (P = 0.001) in data that h ad been conditioned for allele sharing at the CTLA-4 locus under an epistat ic model. There was no evidence to support linkage of GD to Xq21.33-q22 (GD 3) or at the 14q31-q33 (GD1) region in our population. A locus with a moder ate contribution to GD susceptibility (lambda (s) = 1.4) is likely to exist in the Xp11 region, but we are unable to confirm that the GD1 or the GD3 r egions contain major susceptibility loci in our United Kingdom GD populatio n.