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
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. We performed the first two-stage GWAS of T1D usi...
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| Published in | Diabetes care Vol. 42; no. 8; pp. 1414 - 1421 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
American Diabetes Association
01.08.2019
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 0149-5992 1935-5548 1935-5548 |
| DOI | 10.2337/dc18-2023 |
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| Abstract | 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.
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.
We observed a high genetic correlation between children/adolescents and adult T1D case subjects (
= 0.87), as well as subgroups of autoantibody status (
≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near
(odds ratio [OR] 1.26,
= 2.70 × 10
) and rs3802604 in
(OR 1.24,
= 2.06 × 10
), and two previously reported loci, rs1770 in MHC (OR 4.28,
= 2.25 × 10
) and rs705699 in
(OR 1.46,
= 7.48 × 10
). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus
= 9.78 × 10
), 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 (
= 9.08 × 10
) and lower fasting C-peptide levels (
= 7.19 × 10
) in individuals newly diagnosed with T1D.
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. |
|---|---|
| AbstractList | 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. 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.OBJECTIVEType 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.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.RESEARCH DESIGN AND METHODSWe 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.We observed a high genetic correlation between children/adolescents and adult T1D case subjects (r g = 0.87), as well as subgroups of autoantibody status (r g ≥ 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.RESULTSWe observed a high genetic correlation between children/adolescents and adult T1D case subjects (r g = 0.87), as well as subgroups of autoantibody status (r g ≥ 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.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.CONCLUSIONSOur results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine. 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. 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. We observed a high genetic correlation between children/adolescents and adult T1D case subjects ( = 0.87), as well as subgroups of autoantibody status ( ≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near (odds ratio [OR] 1.26, = 2.70 × 10 ) and rs3802604 in (OR 1.24, = 2.06 × 10 ), and two previously reported loci, rs1770 in MHC (OR 4.28, = 2.25 × 10 ) and rs705699 in (OR 1.46, = 7.48 × 10 ). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus = 9.78 × 10 ), 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 ( = 9.08 × 10 ) and lower fasting C-peptide levels ( = 7.19 × 10 ) in individuals newly diagnosed with T1D. 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. |
| Author | Gu, Wei Yang, Tao Hu, Zhibin Chen, Yang Xu, Xinyu Li, Xin Shen, Min Ni, Shining Shi, Yun Luo, Feihong Cai, Yun Dai, Hao Liu, Yu Huang, Qianwen Ma, Hongxia Jiang, Yue Zhu, Meng Xu, Jingjing Chen, Heng Huang, Gan Li, Yuxiu Zheng, Shuai Zheng, Xuqin Chen, Shuang Yu, Liping Zhu, Jing Fan, Jingyi She, Jin-Xiong Shen, Hongbing Ji, Li Polychronakos, Constantin Hsu, Hsiang-Ting Xu, Haixia Xie, Zhiguo Bian, Lingling Xiao, Lei Gu, Yong Zhou, Hongwen Hu, Ji Fu, Qi Sun, Chengjun Fang, Chen Liu, Jin Jiang, Hemin Zhang, Mei Jiang, Zhu Jin, Guangfu Dai, Juncheng Zhou, Zhiguang Xu, Kuanfeng Sun, Min Weng, Jianping Li, Xia |
| Author_xml | – sequence: 1 givenname: Meng surname: Zhu fullname: Zhu, Meng organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China, State Key Laboratory of Reproductive Medicine, Center for Global Health, Nanjing Medical University, Nanjing, China, Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China – sequence: 2 givenname: Kuanfeng surname: Xu fullname: Xu, Kuanfeng organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 3 givenname: Yang surname: Chen fullname: Chen, Yang organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 4 givenname: Yong surname: Gu fullname: Gu, Yong organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 5 givenname: Mei orcidid: 0000-0003-0227-4323 surname: Zhang fullname: Zhang, Mei organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 6 givenname: Feihong surname: Luo fullname: Luo, Feihong organization: Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children’s Hospital of Fudan University, Shanghai, China – sequence: 7 givenname: Yu surname: Liu fullname: Liu, Yu organization: Department of Endocrinology and Metabolism, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China – sequence: 8 givenname: Wei surname: Gu fullname: Gu, Wei organization: Department of Endocrinology, Children’s Hospital of Nanjing Medical University, Nanjing, China – sequence: 9 givenname: Ji surname: Hu fullname: Hu, Ji organization: Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Soochow University, Suzhou, China – sequence: 10 givenname: Haixia surname: Xu fullname: Xu, Haixia organization: Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China – sequence: 11 givenname: Zhiguo surname: Xie fullname: Xie, Zhiguo organization: Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China, National Clinical Research Center for Metabolic Diseases, Changsha, China, Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha, China – sequence: 12 givenname: Chengjun surname: Sun fullname: Sun, Chengjun organization: Department of Pediatric Endocrinology and Inherited Metabolic Diseases, Children’s Hospital of Fudan University, Shanghai, China – sequence: 13 givenname: Yuxiu surname: Li fullname: Li, Yuxiu organization: Department of Endocrinology, Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China – sequence: 14 givenname: Min surname: Sun fullname: Sun, Min organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 15 givenname: Xinyu surname: Xu fullname: Xu, Xinyu organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 16 givenname: Hsiang-Ting surname: Hsu fullname: Hsu, Hsiang-Ting organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 17 givenname: Heng surname: Chen fullname: Chen, Heng organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 18 givenname: Qi surname: Fu fullname: Fu, Qi organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 19 givenname: Yun surname: Shi fullname: Shi, Yun organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 20 givenname: Jingjing surname: Xu fullname: Xu, Jingjing organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 21 givenname: Li surname: Ji fullname: Ji, Li organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 22 givenname: Jin surname: Liu fullname: Liu, Jin organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 23 givenname: Lingling surname: Bian fullname: Bian, Lingling organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 24 givenname: Jing surname: Zhu fullname: Zhu, Jing organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 25 givenname: Shuang surname: Chen fullname: Chen, Shuang organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 26 givenname: Lei surname: Xiao fullname: Xiao, Lei organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 27 givenname: Xin surname: Li fullname: Li, Xin organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 28 givenname: Hemin surname: Jiang fullname: Jiang, Hemin organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 29 givenname: Min surname: Shen fullname: Shen, Min organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 30 givenname: Qianwen surname: Huang fullname: Huang, Qianwen organization: Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China – sequence: 31 givenname: Chen surname: Fang fullname: Fang, Chen organization: Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Soochow University, Suzhou, China – sequence: 32 givenname: Xia surname: Li fullname: Li, Xia organization: Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China, National Clinical Research Center for Metabolic Diseases, Changsha, China, Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha, China – sequence: 33 givenname: Gan surname: Huang fullname: Huang, Gan organization: Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China, National Clinical Research Center for Metabolic Diseases, Changsha, China, Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha, China – sequence: 34 givenname: Jingyi surname: Fan fullname: Fan, Jingyi organization: State Key Laboratory of Reproductive Medicine, Center for Global Health, Nanjing Medical University, Nanjing, China – sequence: 35 givenname: Zhu surname: Jiang fullname: Jiang, Zhu organization: State Key Laboratory of Reproductive Medicine, Center for Global Health, Nanjing Medical University, Nanjing, China – sequence: 36 givenname: Yue surname: Jiang fullname: Jiang, Yue organization: State Key Laboratory of Reproductive Medicine, Center for Global Health, Nanjing Medical University, Nanjing, China – sequence: 37 givenname: Juncheng surname: Dai fullname: Dai, Juncheng organization: State Key Laboratory of Reproductive Medicine, Center for Global Health, Nanjing Medical University, 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fullname: Zhou, Hongwen organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China – sequence: 44 givenname: Shining surname: Ni fullname: Ni, Shining organization: Department of Endocrinology, Children’s Hospital of Nanjing Medical University, Nanjing, China – sequence: 45 givenname: Guangfu surname: Jin fullname: Jin, Guangfu organization: State Key Laboratory of Reproductive Medicine, Center for Global Health, Nanjing Medical University, Nanjing, China, Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China – sequence: 46 givenname: Jin-Xiong surname: She fullname: She, Jin-Xiong organization: Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA – sequence: 47 givenname: Liping orcidid: 0000-0003-0664-2154 surname: Yu fullname: Yu, Liping organization: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO – sequence: 48 givenname: Constantin orcidid: 0000-0002-7624-6635 surname: Polychronakos fullname: Polychronakos, Constantin organization: The Endocrine Genetics Laboratory, Child Health and Human Development Program and Department of Pediatrics, McGill University Health Centre Research Institute, Montreal, Canada – sequence: 49 givenname: Zhibin surname: Hu fullname: Hu, Zhibin organization: State Key Laboratory of Reproductive Medicine, Center for Global Health, Nanjing Medical University, Nanjing, China, Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China – sequence: 50 givenname: Zhiguang orcidid: 0000-0002-0374-1838 surname: Zhou fullname: Zhou, Zhiguang organization: Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China, National Clinical Research Center for Metabolic Diseases, Changsha, China, Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, Changsha, China – sequence: 51 givenname: Jianping orcidid: 0000-0003-2705-196X surname: Weng fullname: Weng, Jianping organization: Department of Endocrinology and Metabolism, Guangdong Provincial Key Laboratory of Diabetology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China – sequence: 52 givenname: Hongbing surname: Shen fullname: Shen, Hongbing organization: State Key Laboratory of Reproductive Medicine, Center for Global Health, Nanjing Medical University, Nanjing, China, Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, China – sequence: 53 givenname: Tao orcidid: 0000-0001-6375-3622 surname: Yang fullname: Yang, Tao organization: Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China, Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China |
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| Copyright | 2019 by the American Diabetes Association. Copyright American Diabetes Association Aug 1, 2019 |
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| Snippet | 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... OBJECTIVE Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although... |
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| Title | 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 |
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