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
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 × 10−8) and rs3802604 in GATA3 (OR 1.24, P = 2.06 × 10−8), and two previously reported loci, rs1770 in MHC (OR 4.28, P = 2.25 × 10−232) and rs705699 in SUOX (OR 1.46, P = 7.48 × 10−20). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus P = 9.78 × 10−12), 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 × 10−11) and lower fasting C-peptide levels (P = 7.19 × 10−3) 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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Glutamic acid decarboxylase antibody positivity is frequently observed in adult-onset type 1 diabetes mellitus.
“Glutamic acid decarboxylase antibody positivity is frequently observed in adult-onset T1DM.”
From The epidemiology of type 1 diabetes mellitus in older adults (2025) · cites this paper as [60]
Adult-onset type 1 diabetes mellitus most often presents with glutamic acid decarboxylase antibody positivity.
“Adult-onset cases most often present with GADA positivity60.”
From The epidemiology of type 1 diabetes mellitus in older adults (2025) · cites this paper as [60]
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- Authors
- Zhu, M., Xu, K., Chen, Y., Gu, Y., Zhang, M., Luo, F., Liu, Y., Gu, W., Hu, J., Xu, H., Xie, Z., Sun, C., Li, Y., Sun, M., Xu, X., Hsu, H.-T., Chen, H., Fu, Q., Shi, Y., Xu, J., Ji, L., Liu, J., Bian, L., Zhu, J., Chen, S., Xiao, L., Li, X., Jiang, H., Shen, M., Huang, Q., Fang, C., Li, X., Huang, G., Fan, J., Jiang, Z., Jiang, Y., Dai, J., Ma, H., Zheng, S., Cai, Y., Dai, H., Zheng, X., Zhou, H., Ni, S., Jin, G., She, J.-X., Yu, L., Polychronakos, C., Hu, Z., Zhou, Z., Weng, J., Shen, H., & Yang, T.
- Affiliations
- Jiangsu Province Hospital (CN)
- Fudan University (CN)
- Nanjing Medical University (CN)
- Second Affiliated Hospital of Nanjing Medical University (CN)
- Second Affiliated Hospital of Soochow University (CN)
- Third Affiliated Hospital of Sun Yat-sen University (CN)
- Central South University (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- State Key Laboratory of Reproductive Medicine (CN)
- Augusta University (US)
- University of Colorado Denver (US)
- McGill University Health Centre (CA)
- ORCID
- Zhu, Meng
- Xu, Kuanfeng
- Chen, Yang
- Gu, Yong
- Zhang, Mei
- Luo, Feihong
- Liu, Yu
- Gu, Wei
- Hu, Ji
- Xu, Haixia
- Xie, Zhiguo
- Sun, Chengjun
- Li, Yuxiu
- Sun, Min
- Xu, Xinyu
- Chen, Heng
- Fu, Qi
- Shi, Yun
- Xu, Jingjing
- Liu, Jin
- Zhu, Jing
- Chen, Shuang
- Xiao, Lei
- Li, Xin
- Jiang, Hemin
- Shen, Min
- Huang, Qianwen
- Fang, Chen
- Li, Xia
- Huang, Gan
- Fan, Jingyi
- Jiang, Yue
- Dai, Juncheng
- Ma, Hongxia
- Zheng, Shuai
- Cai, Yun
- Dai, Hao
- Zheng, Xuqin
- Zhou, Hongwen
- Jin, Guangfu
- She, Jin-Xiong
- Yu, Liping
- Polychronakos, Constantin
- Hu, Zhibin
- Zhou, Zhiguang
- Weng, Jianping
- Shen, Hongbing
- Yang, Tao
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2019-05-31
- Volume
- 42
- Issue
- 8
- Pages
- 1414-1421
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- OpenAlex
- W2947074868
- Cited by
- 100
- References
- 35
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 12 · 2023: 17 · 2022: 17 · 2021: 13 · 2020: 10 · 2019: 6
- FWCI
- 7.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes Care (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- type 1 diabetes, genetic susceptibility loci, age at diagnosis, fasting C-peptide, islet function, MHC region, BTN3A1, GATA3, polygenic risk score, Han Chinese, genetic correlation, fine mapping, novel loci
- MeSH terms
- Butyrophilins, Adolescent, Adult, Age Factors, Autoantibodies, C-Peptide, Child, China, Diabetes Mellitus, Type 1, Fasting, Female, Humans, Male, Risk Factors, Histocompatibility Antigens Class I, Antigens, CD, Odds Ratio, Asian People, Oxidoreductases Acting on Sulfur Group Donors, GATA3 Transcription Factor, Genome-Wide Association Study, Genetic Loci
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