Genome-Wide Association Studies of Autoimmune Thyroid Diseases, Thyroid Function, and Thyroid Cancer

Abstract

Thyroid diseases, including autoimmune thyroid diseases and thyroid cancer, are known to have high heritability. Family and twin studies have indicated that genetics plays a major role in the development of thyroid diseases. Thyroid function, represented by thyroid stimulating hormone (TSH) and free thyroxine (T4), is also known to be partly genetically determined. Before the era of genome-wide association studies (GWAS), the ability to identify genes responsible for susceptibility to thyroid disease was limited. Over the past decade, GWAS have been used to identify genes involved in many complex diseases, including various phenotypes of the thyroid gland. In GWAS of autoimmune thyroid diseases, many susceptibility loci associated with autoimmunity (human leukocyte antigen [HLA], protein tyrosine phosphatase, non-receptor type 22 [PTPN22], cytotoxic T-lymphocyte associated protein 4 [CTLA4], and interleukin 2 receptor subunit alpha [IL2RA]) or thyroid-specific genes (thyroid stimulating hormone receptor [TSHR] and forkhead box E1 [FOXE1]) have been identified. Regarding thyroid function, many susceptibility loci for levels of TSH and free T4 have been identified through genome-wide analyses. In GWAS of differentiated thyroid cancer, associations at FOXE1, MAP3K12 binding inhibitory protein 1 (MBIP)-NK2 homeobox 1 (NKX2-1), disrupted in renal carcinoma 3 (DIRC3), neuregulin 1 (NRG1), and pecanex-like 2 (PCNXL2) have been commonly identified in people of European and Korean ancestry, and many other susceptibility loci have been found in specific populations. Through GWAS of various thyroid-related phenotypes, many susceptibility loci have been found, providing insights into the pathogenesis of thyroid diseases and disease co-clustering within families and individuals.

Keywords: Genome-wide association study; Graves disease; Hashimoto disease; Thyroid function; Thyroid neoplasms.

Fig. 1. Comparison of associations between Europeans and Koreans. The P values for differentiated thyroid cancer (DTC) between Koreans (x-axis) and Europeans (y-axis) are plotted with the corresponding Korean effect sizes (odd ratio [OR]). The P value shows the −log₁₀ scale, and the P values of novel single-nucleotide polymorphisms from this study are compared as unknown. Adapted from Son et al. [54]. FOXE1, forkhead box E1; DIRC3, disrupted in renal carcinoma 3; NKX2-1, NK2 homeobox 1; NRG1, neuregulin 1; DHX35, DEAH-box helicase 35; IMMP2L, inner mitochondrial membrane peptidase subunit 2; ARSB, arylsulfatase B; WDR11-AS1, WDR11 antisense RNA 1; VAV3, vav guanine nucleotide exchange factor 3; PCNXL2, pecanex-like 2; MSRB3, methionine sulfoxide reductase B3; SEPT11, septin 11; FHIT, fragile histidine triad; INSR, insulin receptor.