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Identification of BACH2 as a susceptibility gene for Graves’ disease in the Chinese Han population based on a three-stage genome-wide association study

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Abstract

The BACH2 gene regulates B cell differentiation and function and has been reported to be a shared susceptibility gene for several autoimmune diseases. Our previous genome-wide association study (GWAS) indicated that several single nucleotide polymorphisms (SNPs) in the BACH2 gene are associated with Graves’ disease (GD) in the Chinese Han population; however, the association did not achieve genome-wide significance levels. Recently, this association of BACH2 with GD was confirmed in Caucasians in the UK population, but fine mapping in this region has not yet been reported. Here, we provide a refined analysis of a 331-kb region in the BACH2 gene, which harbors 359 SNPs, using GWAS data from 1,442 GD patients and 1,468 controls. The SNPs rs2474619 and rs9344996 were implied as the independent variants associated with GD by forward and two-locus logistic regression analysis. We genotyped eight out of 10 tagSNPs with P < 1 × 10−3 in 3,508 GD patients and 3,209 controls, the results also showed that rs2474619 was independently associated with GD in the combined population from GWAS and the second stage (P = 1.81 × 10−5). The rs2474619 and rs9344996 were further genotyped in the third stage cohorts, and rs2474619 showed evidence of association with GD at genome-wide significance levels in the combined population (P = 3.28 × 10−8, odds ratio = 1.13). The association of rs9344996 with GD can be explained by its linkage to rs2474619 in the combined population. Our study clearly demonstrated that BACH2 is a susceptibility gene for GD in the Chinese Han population and further supported rs2474619, in intron 2 of BACH2, is the best association signal with GD. However, the mechanism by which BACH2 confers increased risk of GD requires further study.

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Acknowledgments

This work was supported in part by the National Natural Science Foundation of China (grant numbers 81100553, 81200568, 81270863, 81370888, 81000321, 81101444 and 31171127), the National Basic Research Program of China (973) (grant numbers 2010CB529204 and 2012CB517604), the Shanghai Jiaotong University (SJTU) School of Medicine (grant number BXJ201208), the Program for Graves’ Disease, the Innovative Research Team of the Shanghai Municipal Education Commission and the Natural Science Foundation of Jiangsu Province, China (grant numbers BK2009208 and SBK201221245). The funders had no role in the study design, collection and analysis of the data, decision to publish or the preparation of the manuscript. Membership of the China Consortium for the Genetics of Autoimmune Thyroid Disease: Huai-Dong Song: State Key Laboratory of Medical Genomics, Molecular Medicine Center, Ruijin Hospital Affiliated to Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China; Shanghai Institute of Endocrinology and Metabolism, Department of Endocrinology, Ruijin Hospital Affiliated to SJTU School of Medicine, Shanghai, China. Shuang-Xia Zhao: State Key Laboratory of Medical Genomics, Molecular Medicine Center, Ruijin Hospital Affiliated to Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China; Shanghai Institute of Endocrinology and Metabolism, Department of Endocrinology, Ruijin Hospital Affiliated to SJTU School of Medicine, Shanghai, China. Chun-Ming Pan: State Key Laboratory of Medical Genomics, Molecular Medicine Center, Ruijin Hospital Affiliated to Shanghai Jiaotong University (SJTU) School of Medicine, Shanghai, China. Jun Liang: Department of Endocrinology, The Central Hospital of Xuzhou Affiliated to Xuzhou Medical College, Xuzhou, Jiangsu Province, China. Xiao-Mei Zhang: Department of Endocrinology, The First Hospital Affiliated to Bengbu Medical College, Bengbu, Anhui Province, China. Guo-Yue Yuan: Department of Endocrinology, The Hospital Affiliated to Jiangsu University, Zhenjiang, Jiangsu Province, China. Chang-Gui Li: Department of Endocrinology and Gout Laboratory, Medical School Hospital of Qingdao University, Qingdao, Shandong Province, China. Jia-Lun Chen: Shanghai Institute of Endocrinology and Metabolism, Department of Endocrinology, Ruijin Hospital Affiliated to SJTU School of Medicine, Shanghai, China. Guan-Qi Gao: Department of Endocrinology, Linyi People’s Hospital, Linyi, Shandong Province, China. Li-Bin Liu: Department of Endocrinology, Xiehe Hospital Affiliated to Fujian Medical University, Fuzhou, Fujian Province, China. Gang Chen: Department of Endocrinology, Fujian Province Hospital, Fuzhou, Fujian Province, China. Qing Su: Department of Endocrinology, Xin-Hua Hospital Affiliated to SJTU School of Medicine, Shanghai 200092, China. Yong-De Peng: Department of Endocrinology, The First People’s Hospital Affiliated to SJTU School of Medicine, Shanghai, China. Jia-Jun Zhao: Department of Endocrinology, Shandong Province Hospital, Shandong University, Jinan, China. We thank all patients and normal individuals for participating in this study.

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Authors and Affiliations

  1. State Key Laboratory of Medical Genomics, Molecular Medicine Center, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China

    Wei Liu, Hai-Ning Wang, Zhao-Hui Gu, Shao-Ying Yang, Xiao-Ping Ye, Chun-Ming Pan, Shuang-Xia Zhao, Li-Qiong Xue, Hui-Jun Xie, Sha-Sha Yu, Cui-Cui Guo & Huai-Dong Song

  2. Department of Endocrinology, Shanghai Institute of Endocrinology and Metabolism, Ruijin Hospital Affiliated to SJTU School of Medicine, Shanghai, China

    Wei Liu, Shao-Ying Yang, Shuang-Xia Zhao & Huai-Dong Song

  3. Shanghai Center for Systems Biomedicine, SJTU, Shanghai, China

    Zhao-Hui Gu

  4. Department of Endocrinology, People’s Hospital of Linyi, Linyi, Shandong, China

    Wen-Hua Du & Guan-Qi Gao

  5. Department of Endocrinology, The Central Hospital of Xuzhou Affiliated to Xuzhou Medical College, Xuzhou, Jiangsu, China

    Jun Liang

  6. Department of Endocrinology, The First Hospital Affiliated to Bengbu Medical College, Bengbu, Anhui, China

    Xiao-Mei Zhang

  7. Department of Endocrinology, The Hospital Affiliated to Jiangsu University, Zhenjiang, Jiangsu, China

    Guo-Yue Yuan

  8. Department of Endocrinology and Gout Laboratory, Medical School Hospital of Qingdao University, Qingdao, Shandong, China

    Chang-Gui Li

  9. Department of Endocrinology, Xin-Hua Hospital Affiliated to SJTU School of Medicine, Shanghai, 200092, China

    Qing Su

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  1. Wei Liu
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  2. Hai-Ning Wang
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  17. Qing Su
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  18. Guan-Qi Gao
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  19. Huai-Dong Song
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The China Consortium for the Genetics of Autoimmune Thyroid Disease

Corresponding author

Correspondence to Huai-Dong Song.

Additional information

W. Liu, H.-N. Wang, Z.-H. Gu and S.-Y. Yang contributed equally to this work.

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Supplementary material 1 (PDF 198 kb)

Supplementary Table 1. Association results for the imputed and typed SNPs in the ~331-kb region at 6q15 with GD in the genome-wide association.

Supplementary Table 2. The r 2 between 10 tagSNPs and these captured SNPs.

Supplementary Table 3. Two-locus logistic regression analysis results of 10 tagSNPs in GWAS stage.

Supplementary Table 4. Two-locus logistic regression analysis results of 8 tagSNPs in combined GWAS and second replication stage data.

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Liu, W., Wang, HN., Gu, ZH. et al. Identification of BACH2 as a susceptibility gene for Graves’ disease in the Chinese Han population based on a three-stage genome-wide association study. Hum Genet 133, 661–671 (2014). https://doi.org/10.1007/s00439-013-1404-2

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  • DOI: https://doi.org/10.1007/s00439-013-1404-2

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