Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study
Article Figures & Tables
Figures
- Figure 1
Predicted causal effects of DNAm on T2DM. The scatterplot shows the genetic-predicted effects of DNAm intensity on risk for T2DM (y-axis) plotted against observed effect estimates (from the LOLIPOP confirmation phase [x-axis]) at each of 16 top-hit MVPs (see Supplementary Table 7). Effect sizes are log–odds ratios per 1-unit change in normalized methylation intensity aligned to higher observed odds of T2DM.
Tables
- Table 1
Baseline characteristics of participants in the EPIC-Norfolk, LOLIPOP, and FHS study samples
EPIC-Norfolk, discovery phase LOLIPOP, confirmation phase FHS, confirmation phase Incident T2DM Noncase Incident T2DM Noncase Prevalent T2DM Noncase N 563 701 1,074 1,590 403 2,204 Female sex, n (%) 474 (84) 407 (58) 352 (36.3) 507 (31.8) 173 (43.0) 1,245 (56.5) Age (years) 61.6 (8.1) 59.1 (9.2) 52.5 (10.2) 49.9 (9.8) 69.3 (8.4) 65.8 (8.9) Ethnicity European European Indian Asian Indian Asian European European HbA1c (%) 6.5 (1.3) 5.5 (0.33) 5.77 (0.49) 5.37 (0.48) 6.67 (1.15) 5.55 (0.27) HbA1c (mmol/mol) 47.4 (14.2) 36.2 (3.6) 40 (5.4) 35 (5.2) 49 (12.6) 37 (3) BMI (kg/m2) 29.2 (4.5) 25.6 (3.6) 28.9 (4.6) 26.7 (3.9) 31.6 (6.2) 27.7 (5.0) Data are means (SD) unless otherwise indicated.
- Table 2
MVPs associated with incident T2DM at P < 1.0E-07 in EPIC-Norfolk (N = 1,264)
CpG identifier Chr Position OR 95% CI P FDR Gene name Gene position cg19693031 1 144152909 0.52 0.46–0.6 2.7E-21 1.3E-15 TXNIP 3′ UTR cg06500161 21 42529656 1.65 1.45–1.89 6.4E-14 1.5E-08 ABCG1 Body cg14476101 1 120057515 0.67 0.59–0.76 2.8E-10 3.9E-05 PHGDH Body cg14020176 17 70276580 1.63 1.4–1.9 3.3E-10 3.9E-05 SLC9A3R1 3′ UTR cg11024682 17 17670819 1.56 1.35–1.79 6.0E-10 5.7E-05 SREBF1 Body cg06397161 22 38090005 1.51 1.32–1.73 4.5E-09 3.3E-04 SYNGR1 Body; TSS200 cg00574958 11 68364198 0.69 0.61–0.78 5.2E-09 3.3E-04 CPT1A 5′ UTR cg06235429 11 67129690 1.49 1.3–1.7 5.5E-09 3.3E-04 NDUFV1 TSS1500 cg05778424 17 52524507 1.69 1.42–2.02 7.4E-09 3.9E-04 AKAP1 5′ UTR cg11376147 11 57017774 0.68 0.59–0.77 1.3E-08 6.0E-04 SLC43A1 Body cg04816311 7 1033176 1.51 1.31–1.75 1.7E-08 7.2E-04 C7orf50 Body cg02711608 19 51979804 0.69 0.6–0.79 4.5E-08 1.5E-03 SLC1A5 1st exon; 5′ UTR cg08309687 21 34242466 0.68 0.6–0.78 4.5E-08 1.5E-03 cg13514042 7 1158728 1.42 1.25–1.61 4.5E-08 1.5E-03 cg08994060 10 6254032 0.65 0.55–0.76 5.2E-08 1.6E-03 PFKFB3 Body cg01676795 7 75424284 1.56 1.33–1.84 6.5E-08 1.8E-03 POR Body cg25130381 1 27313308 1.49 1.29–1.73 6.7E-08 1.8E-03 SLC9A1 Body cg11183227 15 89256411 1.49 1.29–1.72 7.0E-08 1.8E-03 MAN2A2 Body Position: by HapMap build 37. OR: odds ratio per 1 SD in methylation intensity. Genes: gene names in which the CpG falls from 1,500 bp upstream of the transcriptional start site to the end of the 3′ UTR as in Illumina’s Infinium Human Methylation 450K BeadChip manifest file. Chr, chromosome; FDR, false discovery rate.
- Table 3
Confirmation of the top 18 T2DM-associated MVPs in LOLIPOP and FHS
CpG identifier Chr Gene Discovery, incident T2DM LOLIPOP, incident T2DM FHS, prevalent T2DM* OR 95% CI OR 95% CI P β SE P cg19693031 1 TXNIP 0.52 0.46–0.6 0.68 0.62–0.75 1.2E-14 −2.6E-02 2.7E-03 1.6E-21 cg06500161 21 ABCG1 1.65 1.45–1.89 1.44 1.31–1.58 2.6E-14 1.5E-02 1.8E-03 7.1E-17 cg14476101 1 PHGDH 0.67 0.59–0.76 0.81 0.75–0.89 3.0E-06 −1.6E-02 3.6E-03 1.5E-05 cg14020176 17 SLC9A3R1 1.63 1.4–1.9 1.14 1–1.29 4.3E-02 5.4E-03 1.5E-03 3.9E-04 cg11024682 17 SREBF1 1.56 1.35–1.79 1.40 1.26–1.57 2.2E-09 8.6E-03 1.6E-03 5.4E-08 cg06397161 22 SYNGR1 1.51 1.32–1.73 1.17 1.06–1.28 1.1E-03 9.6E-03 2.2E-03 1.6E-05 cg00574958 11 CPT1A 0.69 0.61–0.78 0.80 0.74–0.88 1.1E-06 −6.7E-03 7.9E-04 4.8E-17 cg06235429 11 NDUFV1 1.49 1.3–1.7 1.11 1–1.24 5.8E-02 2.4E-03 1.3E-03 6.5E-02 cg05778424 17 AKAP1 1.69 1.42–2.02 1.44 1.21–1.71 3.5E-05 4.9E-03 1.6E-03 2.5E-03 cg11376147 11 SLC43A1 0.68 0.59–0.77 0.85 0.74–0.97 1.5E-02 −3.2E-03 1.2E-03 8.4E-03 cg04816311 7 C7orf50 1.51 1.31–1.75 1.13 1–1.27 4.4E-02 2.0E-02 3.2E-03 8.4E-10 cg02711608 19 SLC1A5 0.69 0.6–0.79 0.84 0.76–0.93 9.7E-04 −7.9E-03 1.7E-03 2.0E-06 cg08309687 21 — 0.68 0.6–0.78 0.82 0.74–0.91 1.9E-04 −7.8E-03 3.0E-03 1.0E-02 cg13514042 7 — 1.42 1.25–1.61 1.04 0.94–1.15 4.4E-01 1.8E-04 1.4E-03 9.0E-01 cg08994060 10 PFKFB3 0.65 0.55–0.76 0.81 0.72–0.92 6.6E-04 −1.6E-02 2.5E-03 8.5E-10 cg01676795 7 POR 1.56 1.33–1.84 1.09 0.95–1.26 2.2E-01 9.2E-03 2.4E-03 1.2E-04 cg25130381 1 SLC9A1 1.49 1.29–1.73 1.23 1.09–1.39 1.2E-03 6.5E-03 1.7E-03 1.7E-04 cg11183227 15 MAN2A2 1.49 1.29–1.72 1.08 0.97–1.2 1.9E-01 4.6E-03 2.0E-03 2.2E-02 MVPs and individual cells with confirmed association P < 0.05 appear in boldface type. FHS: 403 case and 2,204 control subjects). LOLIPOP: 1,074 case and 1,590 control subjects. OR: odds ratio for T2DM per 1 SD in methylation intensity. Chr, chromosome.
* In FHS, β indicates difference in percentage DNAm intensity between case and control subjects, with adjustment for age, sex, principal components 1–3 (calculated from methylation data), batch, and family structure.
- Table 4
Analysis of the top 18 T2DM-associated MVPs in nonblood tissues
CpG identifier Chr Gene Blood, T2DM-CON Liver, T2DM-CON Fat Muscle T2DM CON T2DM-CON T2DM-CON P T2DM-CON, consistent T2DM CON T2DM-CON T2DM-CON P T2DM-CON, consistent OR P T2DM-CON P Consistent cg19693031 1 TXNIP 0.52 2.7E-21 −0.041 0.65 True 0.501 0.499 0.002 0.71 False 0.594 0.634 -0.040 0.02 True cg06500161 21 ABCG1 1.65 6.4E-14 0.035 0.64 True 0.477 0.439 0.038 0.02 True 0.360 0.349 0.011 0.75 True cg14476101 1 PHGDH 0.67 2.8E-10 0.080 0.14 False 0.565 0.561 0.004 0.86 False 0.483 0.484 −0.001 0.85 True cg14020176 17 SLC9A3R1 1.63 3.3E-10 0.065 0.26 True 0.678 0.686 −0.008 0.36 False 0.741 0.748 −0.007 0.52 False cg11024682 17 SREBF1 1.56 6.0E-10 0.081 0.24 True 0.646 0.640 0.007 0.58 True 0.406 0.391 0.016 0.96 True cg06397161 22 SYNGR1 1.51 4.5E-09 −0.145 0.07 False 0.501 0.516 −0.015 0.09 False 0.562 0.566 −0.005 0.78 False cg00574958 11 CPT1A 0.69 5.2E-09 0.059 0.42 FALSE 0.091 0.096 −0.005 0.22 True 0.097 0.103 −0.006 0.33 True cg06235429 11 NDUFV1 1.49 5.5E-09 −0.037 0.60 False 0.793 0.793 0.001 0.43 True 0.764 0.765 −0.001 0.82 False cg05778424 17 AKAP1 1.69 7.4E-09 0.019 0.75 True 0.583 0.594 −0.011 0.36 False 0.644 0.648 −0.005 0.64 False cg11376147 11 SLC43A1 0.68 1.3E-08 0.076 0.15 False 0.301 0.305 −0.005 0.54 True 0.282 0.285 −0.003 0.64 True cg04816311 7 C7orf50 1.51 1.7E-08 0.026 0.63 True 0.853 0.861 −0.008 0.81 False 0.879 0.885 −0.006 0.35 False cg02711608 19 SLC1A5 0.69 4.5E-08 0.018 0.72 False 0.245 0.256 −0.011 0.06 True 0.356 0.376 −0.020 0.06 True cg08309687 21 0.68 4.5E-08 0.017 0.85 False 0.634 0.653 −0.019 0.12 True 0.446 0.445 0.001 0.85 False cg13514042 7 1.42 4.5E-08 0.130 0.09 True 0.710 0.706 0.003 0.71 True 0.732 0.724 0.007 0.55 True cg08994060 10 PFKFB3 0.65 5.2E-08 −0.095 0.17 True 0.170 0.175 −0.005 0.86 True 0.154 0.143 0.011 0.55 False cg01676795 7 POR 1.56 6.5E-08 −0.090 0.47 False 0.851 0.852 −0.001 0.86 False 0.890 0.892 −0.002 0.85 False cg25130381 1 SLC9A1 1.49 6.7E-08 −0.069 0.14 False 0.621 0.610 0.011 0.19 True 0.764 0.776 −0.011 0.40 False cg11183227 15 MAN2A2 1.49 7.0E-08 −0.105 0.19 False 0.945 0.946 −0.001 0.63 False 0.906 0.910 −0.004 0.40 False Data are mean β unless otherwise indicated. CON, control subjects.
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