Robust evidence for five new Graves' disease risk loci from a staged genome-wide association analysis

• Published in: Human molecular genetics 2013-08, Vol.22 (16), p.3347-3362
• Main Authors: Zhao, Shuang-Xia, Xue, Li-Qiong, Liu, Wei, Gu, Zhao-Hui, Pan, Chun-Ming, Yang, Shao-Ying, Zhan, Ming, Wang, Hai-Ning, Liang, Jun, Gao, Guan-Qi, Zhang, Xiao-Mei, Yuan, Guo-Yue, Li, Chang-Gui, Du, Wen-Hua, Liu, Bing-Li, Liu, Li-Bin, Chen, Gang, Su, Qing, Peng, Yong-De, Zhao, Jia-Jun, Ning, Guang, Huang, Wei, Liang, Liming, Qi, Lu, Chen, Sai-Juan, Chen, Zhu, Chen, Jia-Lun, Song, Huai-Dong
• Format: Article
• Language: English
• Subjects: ABO Blood-Group System - genetics; ABO system; Adult; Antigens, CD - genetics; Base Sequence; Case-Control Studies; Collagen; DNA, Intergenic; Female; Genetic Loci; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Graves Disease - genetics; Humans; Male; Membrane Proteins - genetics; Middle Aged; Molecular Sequence Data; Polymorphism, Single Nucleotide; Receptors, Cell Surface - genetics; Receptors, G-Protein-Coupled - genetics; RNA, Untranslated - genetics; Signaling Lymphocytic Activation Molecule Family; Signaling Lymphocytic Activation Molecule Family Member 1; Tumor Necrosis Factors - genetics
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddt183

Graves' disease (GD), characterized by autoantibodies targeting antigens specifically expressed in thyroid tissues causing hyperthyroidism, is triggered by a combination of genetic and environmental factors. However, only a few loci for GD risk were confirmed in the various ethnic groups, and additional genetic determinants have to be detected. In this study, we carried out a three-stage study in 9529 patients with GD and 9984 controls to identify new risk loci for GD and found genome-wide significant associations in the overall populations for five novel susceptibility loci: the GPR174-ITM2A at Xq21.1, C1QTNF6-RAC2 at 22q12.3-13.1, SLAMF6 at 1q23.2, ABO at 9q34.2 and an intergenic region harboring two non-coding RNAs at 14q32.2 and one previous indefinite locus, TG at 8q24.22 (Pcombined < 5 × 10(-8)). The genotypes of corresponding variants at 14q32.2 and 8q24.22 were correlated with the expression levels of C14orf64 and a TG transcript skipping exon 46, respectively. This study increased the number of GD loci with compelling evidence and indicated that non-coding RNAs might be potentially involved in the pathogenesis of GD.