TY - JOUR
T1 - Identification of novel T1D risk loci and their association with age and islet function at diagnosis in autoantibody-positive T1D individuals
T2 - Based on a two-stage genome-wide association study
AU - Zhu, Meng
AU - Xu, Kuanfeng
AU - Chen, Yang
AU - Gu, Yong
AU - Zhang, Mei
AU - Luo, Feihong
AU - Liu, Yu
AU - Gu, Wei
AU - Hu, Ji
AU - Xu, Haixia
AU - Xie, Zhiguo
AU - Sun, Chengjun
AU - Li, Yuxiu
AU - Sun, Min
AU - Xu, Xinyu
AU - Hsu, Hsiang Ting
AU - Chen, Heng
AU - Fu, Qi
AU - Shi, Yun
AU - Xu, Jingjing
AU - Ji, Li
AU - Liu, Jin
AU - Bian, Lingling
AU - Zhu, Jing
AU - Chen, Shuang
AU - Xiao, Lei
AU - Li, Xin
AU - Jiang, Hemin
AU - Shen, Min
AU - Huang, Qianwen
AU - Fang, Chen
AU - Li, Xia
AU - Huang, Gan
AU - Fan, Jingyi
AU - Jiang, Zhu
AU - Jiang, Yue
AU - Dai, Juncheng
AU - Ma, Hongxia
AU - Zheng, Shuai
AU - Cai, Yun
AU - Dai, Hao
AU - Zheng, Xuqin
AU - Zhou, Hongwen
AU - Ni, Shining
AU - Jin, Guangfu
AU - She, Jin Xiong
AU - Yu, Liping
AU - Polychronakos, Constantin
AU - Hu, Zhibin
AU - Zhou, Zhiguang
AU - Weng, Jianping
AU - Shen, Hongbing
AU - Yang, Tao
N1 - Funding Information:
Acknowledgments. The authors gratefully acknowledge the WTCCC group for generously allowing the use of their genotype data. The authors thank all the study participants, research staff, and students who participated in this work. Funding. This work was supported in part by the National Key Project of Research and Development Plan (2016YFC1000204, 2016YFC1305302, 2016YFC1305000, and 2016YFC1305001), the NationalKeyTechnologiesR&DProgramofChina (2015BAI12B13), the Innovation-Driven Program of Central South University (2015CX009), the Cheung Kong Scholars Program of China, the Key Program of National Natural Science Foundation of China (81830023, 81530026, and 81530025), the National Natural Science Foundation of China (81390543, 81270897, 81670715, 81670756, 81370939, 81300668, 81400808, 81400813, and 81803306), the Jiangsu Specially Appointed Professor project, the Science and Technology Innovation Team of Jiangsu Province Qinglan Project, the Priority Academic Program for the Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine), the Top-Notch Academic Programs Project of Jiangsu Higher Education Institutions (PPZY2015A067), the Jiangsu Province Key Science and Technology Development Project (BE2017753), the Jiangsu Province Science Foundation for Youth (BK20171082 and BK20180675), the Three Big Constructions funds of Sun Yat-sen University (82000-31133402), the Science and Technology Commission of Shanghai Municipality (STCSM 15411961700), and the Beijing Science and Technology project (Z151100003915077). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. M. Zhu performed statistical analyses, drafted the initial manuscript, and revised the manuscript. K.X. participated in study design, performed overall project management, and revised the manuscript. Y.Ch. and Y.G. performed overall project management and sample processing. M.Zha., M.Su., X.X., S.Z., Y.Ca., H.D., and X.Z. were responsible for control recruitment and sample preparation in the validation stage. F.L., J.H., C.S., and C.F. contributed to the sample recruitment from southeast China. Y. Liu, Z.X., Y. Li, Xia Li, and G.H. were responsible for the preparation of samples from central China. W.G., H.C., Q.F., Y.S., J.X., L.J., J.L., L.B., J.Z., S.C., L.X., Xin Li, H.J., M.Sh., and S.N. were responsible for subject recruitment and sample preparation in the GWAS stage. H.X. and Q.H. contributed to the sample recruitment andsamplepreparationfromsouthChina.H.T.H., Y.J., J.D., H.M., and G.J. contributed to discussion and helped edit the manuscript. J.F. and Z.J. carried out genotyping. H.Z., J.-X.S., L.Y., and C.P. reviewed and commented on various versions of the manuscript and suggested revisions. Z.H., Z.Z., J.W., H.S., and T.Y. directed the study, obtained financial support, and were responsible for study design. M. Zhu, K.X., Y.Ch., Y.G., M.Zha., F.L., Y. Liu, W.G., J.H., H.X., Z.X., C.S., Y. Li, M.Su., X.X., H.T.H., H.C., Q.F., Y.S., J.X., L.J., J.L., L.B., J.Z., S.C., L.X., Xin Li, H.J., M.Sh., G.H., C.F., Xia Li, G.H., J.F., Z.J., Y.J., J.D., H.M., S.Z., Y.Ca., H.D., X.Z., H.Z., S.N., G.J., J.-X.S., L.Y., C.P., Z.H., Z.Z., J.W., H.S., and T.Y. approved the final manuscript.T.Y.istheguarantorofthisworkand, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented in abstract form at the 78th Scientific Sessions of the American Diabetes Association, Orlando, FL, 22–26 June 2018.
Publisher Copyright:
© 2019 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - OBJECTIVE Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified >60 T1D loci in Caucasians, less is known in Asians. RESEARCH DESIGN AND METHODS We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis. RESULTS We observed a high genetic correlation between children/adolescents and adult T1D case subjects (rg = 0.87), as well as subgroups of autoantibody status (rg ‡ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near BTN3A1 (odds ratio [OR] 1.26, P = 2.70 3 1028) and rs3802604 in GATA3 (OR 1.24, P = 2.06 3 1028), and two previously reported loci, rs1770 in MHC (OR 4.28, P = 2.25 3 102232) and rs705699 in SUOX (OR 1.46, P = 7.48 3 10220). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus P = 9.78 3 10212), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85-0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (P = 9.08 3 10211) and lower fasting C-peptide levels (P = 7.19 3 1023) in individuals newly diagnosed with T1D. CONCLUSIONS Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine.
AB - OBJECTIVE Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified >60 T1D loci in Caucasians, less is known in Asians. RESEARCH DESIGN AND METHODS We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis. RESULTS We observed a high genetic correlation between children/adolescents and adult T1D case subjects (rg = 0.87), as well as subgroups of autoantibody status (rg ‡ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near BTN3A1 (odds ratio [OR] 1.26, P = 2.70 3 1028) and rs3802604 in GATA3 (OR 1.24, P = 2.06 3 1028), and two previously reported loci, rs1770 in MHC (OR 4.28, P = 2.25 3 102232) and rs705699 in SUOX (OR 1.46, P = 7.48 3 10220). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus P = 9.78 3 10212), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85-0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (P = 9.08 3 10211) and lower fasting C-peptide levels (P = 7.19 3 1023) in individuals newly diagnosed with T1D. CONCLUSIONS Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine.
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U2 - 10.2337/dc18-2023
DO - 10.2337/dc18-2023
M3 - Article
C2 - 31152121
AN - SCOPUS:85070183309
SN - 0149-5992
VL - 42
SP - 1414
EP - 1421
JO - Diabetes Care
JF - Diabetes Care
IS - 8
ER -
