Power analysis showed that our study was able to detect common genetic variants with moderate to large effects, but was underpowered to detect variants with small effects (Supplementary Fig.?3). variants that predispose to both antibodies: rs13190616 inside (P?=?2.01??10?6), rs561030786 close to (P?=?7.33??10?6) and rs12713034 HIF-C2 inside (P?=?7.66??10?6). All recognized genomic regions possess a substantial literature record of involvement with female-related characteristics, immune-mediated diseases and personality characteristics that are all characterized by improved thyroid antibody levels. Our findings demonstrate the presence of genetic overlap between thyroid autoimmunity in HT and different non-thyroid diseases characterized by the presence of thyroid antibodies. We also suggest that genetic variants that regulate antibody levels may differ between HT patients and individuals with normal thyroid function. Introduction Hashimotos thyroiditis (HT), also known as chronic lymphocytic thyroiditis or autoimmune thyroiditis, is the most common autoimmune thyroid disorder (AITD) characterized by the infiltration of lymphocytes in the interstitium among the thyrocytes and destruction of thyroid tissue1,2. Another distinguished feature of HT is the presence of elevated thyroid antibodies against two major thyroid antigens – thyroglobulin (Tg) and thyroid peroxidase (TPO)3. Tg is usually a large homodimeric glycoprotein synthesized by thyrocytes and secreted into the follicular lumen4. It is involved both in the synthesis and in the storage of thyroid hormones – triiodothyronine (T3) and thyroxine (T4)4. TPO is a homodimeric membrane-bound enzyme also involved in the synthesis of thyroid hormones5. TPO plays a role in the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT) as it catalyzes iodination of thyrosine residues. TPO also catalyzes coupling of MIT and DIT in Tg, which results in the formation of T3 and T46. Although Tg and TPO are HIF-C2 different antigens, antibodies against Tg (TgAbs) and TPO (TPOAbs) have many common features7. Both TPOAb and TgAb are mostly of immunoglobulin (Ig) G class and exhibit high affinities for their antigens7. TPOAbs are present in about 90% and TgAbs in about 80% of HT patients7,8. Both thyroid antibodies serve as key clinical markers for detection of HT, however TPOAbs are considered as best predictors for thyroid autoimmunity1. Although thyroid antibodies are markers for thyroid damage, it is considered that they are not causative factors and most likely do not have a key role in the pathogenesis of HT8,9. Nevertheless, it is known that TPOAbs can fix complement and therefore cause further damage to thyrocytes by an antibody-dependent cell cytotoxic mechanism7,10. However, it is most likely that this TPOAb-dependent cell cytotoxicity does not have such high impact in overall thyroid destruction as T-cell mediated cytotoxicity does8. On the other hand, it is considered that TgAbs do not cause any damage to thyroid tissue5. Thyroid autoimmunity is not solely associated with thyroid diseases but also with other common autoimmune and non-autoimmune diseases5. In general, circulating TgAb and TPOAb antibodies are detected in 9C25% of non-AITD patients11, but are higher in frequency among patients with autoimmune Mouse Monoclonal to Rabbit IgG diseases such as rheumatoid arthritis12, type 1 diabetes13,14, celiac disease15, polycystic ovary syndrome (PCOS)16,17, systemic lupus erythematosus (SLE)18, and other diseases such as asthma19C21 and urticaria18. A role of thyroid antibodies is also suggested with mood disorders, anxiety and depression22. Finally, of the malignancies, one of the most investigated associations is usually between HIF-C2 thyroid antibodies and breast cancer (BC) where several studies pointed out that thyroid autoimmunity confers a greater risk for development of BC23C26. Thyroid antibodies have strong genetic background and it has been estimated that genetic factors contribute to about 70% of the susceptibility to develop thyroid antibodies27. So far, there were three genome-wide association studies (GWAS) that investigated genetic variants associated with TPOAb levels/positivity in general population; two HIF-C2 of these studies were performed in European population28,29 and one was performed in Korean population30. Altogether, these studies identified.