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A Genome-Wide Scan for Autoimmune Thyroiditis in the Old Order Amish: Replication of Genetic Linkage on Chromosome 5q11.2-q14.3

Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine (E.M.A., M.M.S., T.I.P., K.D.S., B.D.M., A.R.S.), Baltimore, Maryland 21201; Department of Medicine, University of California School of Medicine (W.-C.H.), San Francisco, California 99105; Division of Endocrinology and Metabolism, The Johns Hopkins University School of Medicine (P.W.L.), Baltimore, Maryland 21205; Geriatric Research and Education Clinical Center, Veterans Administration Medical Center (A.R.S.), Baltimore, Maryland 21201

Address all correspondence and requests for reprints to: Alan R. Shuldiner, M.D., Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, 660 West Redwood Street, Room 494, Baltimore, Maryland 21201. E-mail: ashuldin{at}medicine.umaryland.edu.

Autoimmune thyroiditis (AITD) is a common disorder characterized by circulating antibodies to epitopes of thyroid tissue and hypothyroidism (Hashimoto's thyroiditis or AITD-hypothyroidism), although many subjects with AITD are euthyroid. Current evidence suggests that AITD is familial and polygenic. We studied AITD in a homogeneous founder Caucasian population, the Old Order Amish of Lancaster County, Pennsylvania. We found autoimmune thyroiditis, defined by the presence of circulating antimicrosomal antibodies, to be relatively common in the Amish, with a prevalence of 22.7%. The prevalence of AITD-hypothyroidism was 9.2%. We performed a genome-wide linkage analysis with 373 short tandem repeat markers in 445 subjects from 29 families. We observed suggestive evidence of linkage of AITD to a locus on chromosome 5q11.2-q14.3 (LOD, 2.30; P = 0.0006 at 94 cM; closest marker, D5S428), a region that was previously reported to be linked to AITD-hypothyroidism in a Japanese study. AITD-hypothyroidism showed a more modest linkage peak to the same region (LOD, 1.46; P = 0.005). Possible linkage (nominal P < 0.01) to autoimmune thyroiditis and/or AITD-hypothyroidism was also detected in five other regions. We conclude that a gene on chromosome 5q11.2-q14.3 is likely to contribute to susceptibility to AITD in the Amish.

This work was supported by NIH Research Grants R01-DK-54261, R01-AR-46838, R01-AG-18728, K24-DK-02673, and K07-CA-67960 and the Baltimore V.A. Geriatric Research and Education Clinical Center.

Present address for E.M.A.: Novo Nordisk Pharmaceuticals, Inc., 100 College Road, West Princeton, New Jersey 08540.

Abbreviations: AFDS, Amish Family Diabetes Study; AITD, autoimmune thyroiditis; AMA, antimicrosomal antibodies; HT, Hashimoto's thyroiditis; MLS, maximum LOD score; TPO, thyroid peroxidase.

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