Identification of type 2 diabetes loci in 433,540 East Asian individuals

Abstract

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)1,2; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells3. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes—NKX6-3 and ANK1—in different tissues4,5,6. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.

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Fig. 1: Two distinct T2D-association signals at the ANK1NKX6-3 locus are associated with expression levels of two transcripts in two tissues.
Fig. 2: Effect size comparison of lead variants identified in this East Asian T2D GWAS BMI-unadjusted meta-analysis and previous European T2D GWAS meta-analysis2.
Fig. 3: rs117624659 at the NKX6-1 locus exhibits allelic differences in transcriptional activity.

Data availability

Summary-level statistics are publicly available on the AGEN consortium website (https://blog.nus.edu.sg/agen/summary-statistics/t2d-2020), and the Accelerating Medicines Partnership T2D portal (http://www.kp4cd.org/dataset_downloads/t2d). A complete list of web resources is available in the Supplementary Information.

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Acknowledgements

This work was supported by subawards (to X.S. and Y.S.C.) from NIDDK U01DK105554 (J. C. Florez). The authors thank all investigators, staff members and study participants for their contributions to all participating studies, including but not limited to: CAGE (T. Ogihara, Y. Yamori, A. Fujioka, C. Makibayashi, S. Katsuya, K. Sugimoto, K. Kamide and R. Morishita); SBCS (R. Courtney, H. Cai, B. Zhang and J. He); and SMC (D.-H. Kim). A full list of funding, and individual and study acknowledgements are available in the Supplementary Information.

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Authors

Contributions

Project coordination (including supervision of all experiments and analyses): K.L.M. and X.S. Manuscript writing: C.N.S., E.-S.T., M.B., M.H., Y.J.K., K.L., K.L.M., X.S. Core and follow-up analyses including NKX6-1 functional work: C.N.S., M.H., Y.J.K., K.L., A.K.I., H.J.P., S.M.B., K.L.M., X.S. eQTL lookups for ANK1/NKX6-3: M.v.d.B., A.L.G. Core DIAMANTE group: J.E.B. (Hispanic), M.B. (European), D.W.B. (African–American), J.C.C. (South Asian), A.M. (European), M.I.M. (European), M.C.Y.N. (African–American), L.E.P. (Hispanic), W. Zhang (South Asian), A.P.M. (trans-ethnic), K.L.M., X.S. Study-level data analyses: Y.T. (AASC, NAGAHAMA), M.H. (BBJ), K.S. (BBJ), X.S. (BES, DC/SP2, SCHS), F.T. (CAGE-Amagasaki, CAGE-GWAS), M.N. (CAGE-KING), C.N.S. (CHNS, CLHNS), K.L. (CKB), F.B. (CKB), Y.J.K. (KARE, KBA), S. Moon (KBA), C.H.T.T. (HKDR), J.Y. (MESA), X.G. (MESA), J. Long (SBC/SWHS), J.F.C. (SCES), V.J.Y.L. (SiMES), S.-H.K. (SNUH), H.S.C. (SMC), C.-H.C. (TWT2D). Individual cohort study design and/or principal investigators for the individual cohorts: M. Igase (AASC), M.A. (BBJ), S. Maeda (BBJ), T. Kadowaki (BBJ), Y.-X.W. (BES), N.K. (CAGE-Amagasaki, CAGE-GWAS), M.Y. (CAGE-KING), K.L.M. (CHNS, CLHNS), R.G.W. (CKB), E.-S.T. (DC/SP2), J. Lee (KBA), B.-J.K. (KARE, KBA), R.C.W.M. (HKDR), J.I.R. (MESA), F.M. (NAGAHAMA), X.-O.S. (SBC/SWHS), C.-Y.C. (SCES), W.-P.K. (SCHS), T.-Y.W. (SiMES), K.-S.P. (SNUH), Y.S.C. (SMC), W.H.H.S. (TaiChi-G), J.Y.W. (TWT2D) Genotyping and/or phenotyping of the studies: K.K. (AASC), A.T. (BBJ), Y.K. (BBJ), T.Y. (BBJ), Y.O. (BBJ), J.B.J. (BES), T. Katsuya. (CAGE-Amagasaki), M. Isono (CAGE-GWAS), S.I. (CAGE-KING), K. Yamamoto (CAGE-KING), A.-G.H. (CHNS), S.D. (CHNS), W.H. (CHNS), J.S. (CHNS), P.G.-L. (CHNS), C.Y. (CKB), Y.G. (CKB), Z.B. (CKB), J. Lv (CKB), L.L. (CKB), Z.C. (CKB), N.R.L. (CLHNS), L.S.A. (CLHNS), J. Liu (DC/SP2), R.M.v.D. (DC/SP2), S.H. (KBA), K. Yoon (KBA), H.-M.J. (KBA), D.M.S. (KBA), G.J. (HKDR), A.O.L. (HKDR), B.T. (HKDR), W.Y.S. (HKDR), J.C.N.C. (HKDR), M.Y.H. (KARE, KBA), Y.-D.I.C. (MESA), T. Kawaguchi (NAGAHAMA), Y.-B.X. (SBC/SWHS), W. Zheng (SBC/SWHS), L.Z. (SCES), C.-C.K. (SCES), M.A.P. (SCHS), M.G. (SCHS), J.-M.Y. (SCHS), C.S. (SiMES), M.-L.C. (SiMES), M.-S.L. (SMC), C.-M.H. (TaiChi-G), L.-M.C. (TaiChi-G), Y.-J.H. (TaiChi-G), L.-C.C. (TWT2D), Y.-T.C. (TWT2D), F.-J.T. (TWT2D), J.I.R. (MESA).

Corresponding authors

Correspondence to Takashi Kadowaki or Robin G. Walters or Bong-Jo Kim or Karen L. Mohlke or Xueling Sim.

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Competing interests

M.v.d.B. was supported by a Novo Nordisk postdoctoral fellowship run in partnership with the University of Oxford, and currently a full-time employee of Novo Nordisk. M.I.M and A.M. are currently employees of Genentech. The other authors declare no competing interests.

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Peer review information Nature thanks Timothy Frayling, Stephen Rich and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Flow chart of study design.

The flow chart shows the different data analyses performed and corresponding summary of association results.

Extended Data Fig. 2 Manhattan plot for East Asian T2D meta-analysis association results in model unadjusted for BMI.

−log10P values from two-sided fixed-effect inverse-variance genome-wide meta-analysis association results for each variant (y axis; maximal Neff = 211,793) was plotted against the genomic position (hg19; x axis). Known T2D loci achieving genome-wide significance (P < 5.0 × 10−8) in our meta-analysis are shown in blue. Loci achieving genome-wide significance that were previously unreported for T2D association are shown in red.

Extended Data Fig. 3 The relationship between effect size and minor allele frequency.

Odds ratios (y axis) and minor allele frequencies (x axis) for 189 primary association signals from the T2D BMI-unadjusted models. Odds ratios are from two-sided fixed-effect inverse-variance meta-analysis on a maximal effective sample size of 211,793.

Extended Data Fig. 4 Regional association plots at three T2D-associated loci with the strongest association P values and more than five distinct association signals in East Asian individuals.

a, INS/IGF2/KCNQ1. b, CDKN2A/B. c, PAX4/LEP. −log10P values were from the two-sided fixed-effect inverse-variance meta-analysis. Distinct signals (P < 1.0 × 10−5 from GCTA conditional analyses) were plotted; Neff values for each distinct signal are reported in Supplementary Table 4. Variants are coloured based on East Asian 1000G Phase 3 LD with the lead variants for each association signal shown as diamonds.

Extended Data Fig. 5 Effect size comparison of lead variants in sex-combined models unadjusted and adjusted for BMI.

At 189 lead variants identified in the East Asian BMI-unadjusted sex-combined T2D meta-analysis, per-allele effect sizes (β) from the BMI-adjusted sex-combined model (T2DadjBMI) were plotted against the BMI-unadjusted sex-combined model (T2DunadjBMI). Both sex-combined models were from two-sided fixed-effect inverse-variance meta-analyses and included the same set of studies for comparable sample size. Each point denotes the per-allele effect size; grey lines, s.e. Effect sizes between the two models are highly correlated with a Pearson correlation coefficient r = 0.99 (Supplementary Table 4).

Extended Data Fig. 6 Regional plots of male-specific T2D-associated locus, ALDH2.

For each plot, −log10P values from association results from two-sided fixed-effect inverse-variance meta-analyses for each variant (y axis) were plotted against the genomic position (hg19; x axis). The lead variant rs12231737 plotted is the lead variant from the BMI-unadjusted male-specific meta-analysis (Neff = 65,202) and also the sex-combined meta-analysis (Neff = 138,947) from the same subset of individuals included in the sex-stratified analyses (female-specific Neff = 70,051). This lead variant rs12231737 is in high LD with rs77768175, identified from the larger BMI-unadjusted sex-combined meta-analysis (East Asian r2 = 0.80). Top, males only; middle, sex-combined; bottom, females only. Variants are shaded according to East Asian 1000G Phase 3 LD with the lead variant shown as a purple diamond.

Extended Data Fig. 7 Effect size comparison of common lead variants (MAF ≥ 5%) identified in this East Asian meta-analysis and a previously published European T2D GWAS meta-analysis.

For 278 unique lead variants with MAF ≥ 5% in both the East Asian and European BMI-unadjusted meta-analyses, per-allele effect sizes (β) from the European T2D GWAS meta-analysis2 (y axis) were plotted against per-allele effect sizes from our East Asian meta-analysis (x axis). Effect sizes from both meta-analyses were from two-sided fixed-effect inverse-variance meta-analyses (maximal Neff = 211,793 for East Asian and 231,436 for European meta-analyses). Each point denotes the per-allele effect size; grey lines, s.e. Variants are coloured purple if they were significant in the East Asian meta-analysis only, green if they were significant in the European meta-analysis only, and blue if they were significant in both the East Asian and European meta-analyses (see Methods and Supplementary Table 7).

Extended Data Fig. 8 Effect size comparison of lead variants identified in East Asian BMI-unadjusted meta-analysis and previously published European T2D GWAS meta-analysis.

For 332 lead variants identified from the two BMI-unadjusted meta-analyses, per-allele effect sizes (β) from a European meta-analysis2 (y axis) were plotted against per-allele effect sizes from our East Asian meta-analysis (x axis). Effect sizes from both meta-analyses were from two-sided fixed-effect inverse-variance meta-analysis (maximal Neff = 211,793 for East Asian and 231,436 for European meta-analyses). Each point denotes the per-allele effect size; grey lines, s.e. a, The 152 lead variants that were significant in the East Asian meta-analysis (purple) or both the East Asian and European meta-analyses (blue). b, The 192 lead variants that were significant in the European meta-analysis (green) or both the East Asian and European meta-analyses (blue). These plots include only one variant per locus, in contrast to Fig. 2 and Extended Data Fig. 7.

Extended Data Fig. 9 Forest plots of BMI-unadjusted meta-analysis association results at the SIX3–SIX2 locus.

Odds ratios (black boxes) and 95% confidence intervals (horizontal lines) for T2D associations at the lead East Asian variant (rs12712928) across ancestries of African-American (AFR), East Asian (EAS), European (EUR)2, Hispanic (HIS), and South Asian (SAS) individuals (a); within four major East Asian populations (b; Chinese, Japanese, Korean, and Malay–Filipino, combined due to small sample sizes); and from each contributing cohort (c). Effect sizes from the East Asian study, ancestry, population, and combined meta-analysis were from two-sided fixed-effect inverse-variance meta-analysis. The size of each box is proportional to the sample size of each contributing study, ancestry or population (Supplementary Table 8). Our East Asian study had >90% power to detect the observed association with a MAF = 0.40, OR = 1.06, and 77,418 T2D cases. Given the number of T2D cases and frequency of rs12712928-C within the other data sets, at 80% power, we can reasonably exclude association OR > 1.07 in EUR and OR > 1.15 in AFR, HIS, and SAS between rs12782928 and T2D. Full study names can be found in Supplementary Table 1 and corresponding sample sizes can be found in Supplementary Table 2.

Extended Data Table 1 Novel lead variants associated with type 2 diabetes in East Asian individuals

Supplementary information

Supplementary Information

This file contains Study Descriptions, Supplementary Table legends, a list of Web Resources, Funding and Acknowledgments and Supplementary References.

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Supplementary Tables

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Spracklen, C.N., Horikoshi, M., Kim, Y.J. et al. Identification of type 2 diabetes loci in 433,540 East Asian individuals. Nature (2020). https://doi.org/10.1038/s41586-020-2263-3

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