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Nat Genet. 2019 Mar;51(3):379-386. doi: 10.1038/s41588-018-0332-4. Epub 2019 Feb 4.

Identification of 28 new susceptibility loci for type 2 diabetes in the Japanese population.

Author information

1
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
2
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
3
Laboratory for Endocrinology, Metabolism and Kidney Diseases, RIKEN Centre for Integrative Medical Sciences, Yokohama, Japan.
4
Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
5
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
6
Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA.
7
Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
8
Graduate School of Medicine, Tohoku University, Sendai, Japan.
9
Center for Epidemiologic Research in Asia, Shiga University of Medical Science, Otsu, Japan.
10
Department of Public Health, Shiga University of Medical Science, Otsu, Japan.
11
Laboratory of Public Health, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan.
12
Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
13
Department of Oral Epidemiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
14
Division of Clinical Research and Epidemiology, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, Iwate, Japan.
15
Department of Hygiene and Preventive Medicine, School of Medicine, Iwate Medical University, Iwate, Japan.
16
Division of Innovation & Education, Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, Iwate, Japan.
17
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan.
18
Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
19
Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
20
Department of Psychiatry, Fujita Health University School of Medicine, Aichi, Japan.
21
Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
22
Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo, Japan.
23
Department of Advanced Genomic and Laboratory Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.
24
Division of Clinical Laboratory and Blood Transfusion, University of the Ryukyus Hospital, Nishihara, Japan.
25
Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
26
Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.
27
Iwate Tohoku Medical Megabank Organization, Disaster Reconstruction Center, Iwate Medical University, Iwate, Japan.
28
Division of Ultrahigh Field MRI, Institute for Biomedical Sciences, Iwate Medical University, Iwate, Japan.
29
Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka, Japan.
30
RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
31
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. yoichiro.kamatani@riken.jp.
32
Kyoto-McGill International Collaborative School in Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. yoichiro.kamatani@riken.jp.
33
Laboratory for Endocrinology, Metabolism and Kidney Diseases, RIKEN Centre for Integrative Medical Sciences, Yokohama, Japan. momoko.horikoshi@riken.jp.
34
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. tyamau-tky@umin.net.
35
Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. kadowaki-3im@h.u-tokyo.ac.jp.
36
Department of Prevention of Diabetes and Lifestyle-Related Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. kadowaki-3im@h.u-tokyo.ac.jp.
37
Department of Metabolism and Nutrition, Mizonokuchi Hospital, Faculty of Medicine, Teikyo University, Tokyo, Japan. kadowaki-3im@h.u-tokyo.ac.jp.

Abstract

To understand the genetics of type 2 diabetes in people of Japanese ancestry, we conducted A meta-analysis of four genome-wide association studies (GWAS; 36,614 cases and 155,150 controls of Japanese ancestry). We identified 88 type 2 diabetes-associated loci (P < 5.0 × 10-8) with 115 independent signals (P < 5.0 × 10-6), of which 28 loci with 30 signals were novel. Twenty-eight missense variants were in linkage disequilibrium (r2 > 0.6) with the lead variants. Among the 28 missense variants, three previously unreported variants had distinct minor allele frequency (MAF) spectra between people of Japanese and European ancestry (MAFJPN > 0.05 versus MAFEUR < 0.01), including missense variants in genes related to pancreatic acinar cells (GP2) and insulin secretion (GLP1R). Transethnic comparisons of the molecular pathways identified from the GWAS results highlight both ethnically shared and heterogeneous effects of a series of pathways on type 2 diabetes (for example, monogenic diabetes and beta cells).

PMID:
30718926
DOI:
10.1038/s41588-018-0332-4
[Indexed for MEDLINE]

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