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Genome-Wide Scan of Graves’ Disease: Evidence for Linkage on Chromosome 5q31 in Chinese Han Pedigrees

Division of Endocrinology and Metabolism (Y.J., W.T.), Department of Medicine, First Affiliated Hospital to China Medical University, Shenyang 110001, PR China; Chinese National Human Genome Center at Shanghai (Y.J., S.B., X.X., J.Z., S.X., L.J., W.H.), Shanghai 201203, PR China; Department of Public Health (S.B.), China Medical University, Shenyang 110001, PR China; Rui-Jin Hospital affiliated to Shanghai Second Medical University (J.C., W.H.), Shanghai 200025, PR China; and Department of Epidemiology (Y.Y.S.), Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205

Address all correspondence and requests for reprints to: Dr. Weiping Teng, China Medical University, 92 North 2nd Road, Heping District, Shenyang 110001, PR China. E-mail: tengweiping{at}hotmail.com; or Dr. Wei Huang, Chinese National Human Genome Center at Shanghai, 250 Bi Bo Road, Shanghai 201203, PR China. E-mail: huangwei{at}chgc.sh.cn.

Graves’ disease (GD), which is a common organ-specific autoimmune disorder, is multifactorial and develops in genetically susceptible individuals. Despite many studies of candidate genes, only associations with human leukocyte antigen and cytotoxic T lymphocyte antigen 4 have been generally detected, and the number of susceptibility genes remains unknown. To identify chromosomal regions contributing to GD, we conducted a genome-wide scan on 322 individuals from 54 Chinese Han multiplex GD pedigrees. Parametric linkage analysis revealed the strongest evidence for linkage at D5S436 on chromosome 5q31, with a maximum two-point LOD score of 2.8 and a maximum multipoint LOD score of 2.3. To further assess the significance of this suggestive finding, we typed four additional markers around D5S436 in this chromosome region, and a maximum two-point LOD score of 4.31 and a maximum multipoint LOD score of 4.12 were obtained for marker D5S2090 (with heterogeneity, = 0.38). Nonparametric multipoint analysis also showed significant excess allele sharing, with a P value as low as 0.001, at the same locus. Our findings provide evidence for a susceptibility locus for GD on chromosome 5q31 and support the existence of genetic heterogeneity in GD.

This work was supported by grants from the Chinese High-tech Program (863); National Natural Science Foundation Key Program (39993420, 39896200); National Key Program on Basic Research (G1998051002) from the Ministry of Science and Technology; National Natural Science Foundation of China (39970350); and Chinese Medical Board (98-688IITD), People’s Republic of China.

W.T. and W.H. contributed equally to this work.

Abbreviations: AITD, Autoimmune thyroid disease; CTLA-4, cytotoxic T lymphocyte antigen 4; GD, Graves’ disease; HLA, human leukocyte antigen; HT, Hashimoto’s thyroiditis; LOD, limit of detection; NPL, nonparametric linkage.

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