Identification of novel T1D risk loci and their association with age and islet function at diagnosis in autoantibody-positive T1D individuals: Based on a two-stage genome-wide association study

Meng Zhu, Kuanfeng Xu, Yang Chen, Yong Gu, Mei Zhang, Feihong Luo, Yu Liu, Wei Gu, Ji Hu, Haixia Xu, Zhiguo Xie, Chengjun Sun, Yuxiu Li, Min Sun, Xinyu Xu, Hsiang Ting Hsu, Heng Chen, Qi Fu, Yun Shi, Jingjing XuLi Ji, Jin Liu, Lingling Bian, Jing Zhu, Shuang Chen, Lei Xiao, Xin Li, Hemin Jiang, Min Shen, Qianwen Huang, Chen Fang, Xia Li, Gan Huang, Jingyi Fan, Zhu Jiang, Yue Jiang, Juncheng Dai, Hongxia Ma, Shuai Zheng, Yun Cai, Hao Dai, Xuqin Zheng, Hongwen Zhou, Shining Ni, Guangfu Jin, Jin Xiong She, Liping Yu, Constantin Polychronakos, Zhibin Hu, Zhiguang Zhou, Jianping Weng, Hongbing Shen, Tao Yang

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1414-1421
Number of pages8
JournalDiabetes Care
Volume42
Issue number8
DOIs
StatePublished - Aug 1 2019

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialized Nursing

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