Common Variants at 10 Genomic Loci Influence Hemoglobin A1C Levels via Glycemic and Nonglycemic Pathways
Article Figures & Tables
Figures
- FIG. 1.
Manhattan plot and quantile-quantile (QQ) plot of association findings. The figure summarizes the genome-wide association scan results combined across all studies by inverse variance weighting. The blue dotted line marks the threshold for genome-wide significance (5 × 10−8). SNPs in loci exceeding this threshold are highlighted in green. A QQ plot is shown in the inset panel, where the red line corresponds to all test statistics, and the blue line to results after excluding statistics at all associated loci (highlighted in green in the Manhattan plot). The gray area corresponds to the 90% confidence region from a null distribution of P values (generated from 100 simulations). (A high-quality color representation of this figure is available in the online issue.)
- FIG. 2.
Regional association plots at the HbA1c loci. Each panel spans ± 250 kb around the most significant associated SNP in the region, which is highlighted with a blue square (panel C spans ± 300 kb). At the top of each panel, comb diagrams indicate the location of SNPs in the Illumina HumanHap 550K and Affymetrix 500K chips, and of SNPs imputed. The SNPs are colored according to their linkage disequilibrium with the top variant based on the CEU HapMap population (http://www.hapmap.org). Gene transcripts are annotated in the lower box, with the most likely biologic candidate highlighted in blue; ± indicates the direction of transcription. In panel C, a few gene names were omitted for clarity. Here, genes are, from left to right, SCGN, HIST1H2AA, HIST1H2BA, SLC17A4, SLC17A1, SLC17A3, SLC17A2, TRIM38, HIST1H1A, HIST1H3A, HIST1H4A, HIST1H4B, HIST1H3B, HIST1H2AB, HIST1H2BB, HIST1H3C, HIST1H1C, HFE, HIST1H4C, HIST1H1T, HIST1H2BC, HIST1H2AC, HIST1H1E, HIST1H2BD, HIST1H2BD, HIST1H2BE, HIST1H4D, HIST1H3D, HIST1H2AD, HIST1H2BF, HIST1H4E, HIST1H2BG, HIST1H2AE, HIST1H3E, HIST1H1D, HIST1H4F, HIST1H4G, HIST1H3F, HIST1H2BH, HIST1H3G, HIST1H2BI, and HIST1H4H. In panel D, the names of the first two genes, UBE2D4 and WBSCR19, were also omitted for clarity. (A high-quality color representation of this figure is available in the online issue.)
- FIG. 3.
Net reclassification when screening for undiagnosed diabetes, using HbA1c as a population-level measure of genetic effect size. The figure shows the distribution of HbA1c in the FHS and ARIC cohorts combined (N = 10,110), stratified by individuals with undiagnosed type 2 diabetes (UnDx DM, N = 593, black lines) or without diabetes (Non DM, N = 9,517, gray lines), and by HbA1c without adjustment (solid lines) or after adjustment for seven nonglycemic SNPs (dashed lines). The vertical dashed line is the diabetes diagnostic threshold at HbA1c ≥6.5(%). Net reclassification is the overall proportion of the population appropriately moved above or below this line by considering the genetic information. For instance, among individuals with undiagnosed diabetes, 39.5% had an unadjusted HbA1c level ≥6.5 (%) and 37.4% had a seven SNP-adjusted HbA1c level ≥6.5 (%), and among those with undiagnosed diabetes, 2.02% of those with undiagnosed diabetes were misclassified by the influence of the seven SNPs. The net reclassification is calculated as the difference −2.02% − (−0.17%) = −1.86%.
Tables
- TABLE 1
Characteristics of 46,368 participants from 31 cohorts employed in the meta-analysis
Cohort N males/females Age (years) men/women BMI (kg/m2) men/women HbA1C (%, NGSP) men/women Fasting plasma glucose (mmol/l) men/women ARIC 3,106/3,671 57.4 (5.7)/56.7 (5.6) 27.33 (3.89)/26.63 (5.30) 5.41 (0.38)/5.37 (0.36) 5.75 (0.50)/5.52 (0.50) B58C-T1DGC 1,217/1,284 45.3 (0.3)/45.2 (0.3) 27.93 (4.12)/26.86 (5.5) 5.18 (0.48)/5.22 (0.51) — B58C-WTCCC 711/717 44.9 (0.4)/44.9 (0.4) 27.79 (4.21)/26.84 (5.41) 5.21 (0.68)/5.21 (0.51) — BLSA 253/235 72.2 (13.5)/67.2 (15.6) 26.99 (3.92)/25.87 (4.94) 5.44 (0.53)/5.45 (0.45) 5.25 (0.56)/4.99 (0.48) Croatia 275/384 54.8 (15.0)/55.2 (15.8) 27.43 (3.65)/26.94 (4.59) 5.25 (0.49)/5.31 (0.55) 5.40 (0.66)/5.26 (0.65) deCODE 170/172 66.1 (14.4)/63.8 (16.0) 28.20 (4.00)/28.0 (4.90) 5.80 (0.95)/5.77 (1.25) — DESIR 178/538 53.1 (5.6)/49.5 (8.5) 23.15 (1.16)/21.36 (1.85) 5.25 (0.38)/5.16 (0.38) 5.11 (0.32)/5.01 (0.38) DGI 218/262 59.1 (10.6)/59.5 (10.6) 26.42 (3.12)/26.29 (4.29) 5.73 (0.56)/5.61 (0.59) 5.50 (0.52)/5.39 (0.45) DIAGEN 429/571 59.0 (14.2)/59.0 (15.4) 27.08 (3.61)/26.80 (4.82) 5.59 (0.65)/5.50 (0.61) — Epic 5,000 1,732/1,627 57.6 (9.4)/54.0 (9.0) 25.75 (2.60)/24.84 (3.38) 5.19 (0.55)/5.08 (0.55) — EPIC cases 409/548 60.8 (8.9)/60.2 (9.1) 32.55 (2.53)/33.44 (3.24) 5.58 (0.97)/5.47 (0.62) — EPIC cohort 859/1,052 61.3 (9.3)/60.0 (9.2) 26.79 (3.31)/26.33 (4.36) 5.38 (0.56)/5.32 (0.57) — Fenland 606/772 44.4 (7.4)/45.4 (7.2) 27.56 (3.91)/26.59 (5.35) 5.42 (0.37)/5.37 (0.37) 5.01 (0.47)/4.74 (0.48) FHS 886/1,110 54.7 (10.0)/54.1 (9.9) 27.85 (3.92)/26.13 (4.97) 5.24 (0.62)/5.25 (0.61) 5.36 (0.48)/5.14 (0.49 GenomeEUtwin 0/568 —/55.1 (21.8) —/24.6 (4.18) —/5.11 (0.68) —/5.24 (0.55) HEALTH2000 580/625 49.1 (10.4)/51.7 (11.4) 25.69 (3.26)/25.32 (4.19) 5.22 (0.29)/5.06 (0.32) 5.34 (0.48)/5.17 (0.42) Lolipop 582/188 53.2 (10.4)/51.2 (10.5) 27.49 (3.92)/26.74 (5.33) 5.05 (0.54)/5.34 (0.38) 5.51 (1.45)/5.35 (1.75) LURIC 215/195 54.1 (12.6)/61.1 (11.1) 26.90 (3.60)/26.60 (4.00) 5.80 (0.60)/5.90 (0.60) — KORA F3 711/751 62.3 (10.2)/61.6 (10.1) 27.89 (3.49)/27.70 (4.95) 5.30 (0.38)/5.33 (0.31) — KORA S4 844/892 53.9 (8.9)/53.4 (8.8) 27.91 (3.87)/27.25 (4.89) 5.57 (0.46)/5.59 (0.45) — METSIM 1,789/0 57.0 (7.3)/— 26.63 (3.76)/— 5.56 (0.32)/— — NHANES III 468/746 51.3 (20.6)/51.4 (20.3) 26.92 (4.85)/26.37 (5.81) 5.38 (0.50)/5.15 (0.55) — NTR 513/939 47.7 (14.4)/43.3 (13.7) 25.58 (3.28)/24.59 (4.02) 5.27 (0.46)/5.28 (0.45) 5.53 (0.51)/5.32 (0.51) ORCADES 298/353 53.7 (15.3)/52.2 (15.4) 27.79 (4.14)/27.30 (5.11) 5.40 (0.49)/5.41 (0.51) 5.45 (0.51)/5.18 (0.49) Partners/Roche 291/357 52.7 (12.9)/52.5 (12.7) 27.80 (5.20)/27.10 (7.30) 5.49 (0.48)/5.47 (0.45) — PROCARDIS 687/144 60.5 (6.7)/62.8 (6.3) 27.65 (3.58)/28.11 (4.98) 5.98 (1.07)/6.17 (1.10) — SardiNIA 1,418/1,928 46.5 (17.1)/45.2 (16.0) 26.36 (3.99)/24.65 (4.82) 5.47 (0.52)/5.39 (0.45) 4.96 (0.59)/4.67 (0.54) SHIP 1,696/1,842 49.0 (16.0)/47.0 (16.0) 27.30 (3.90)/26.60 (5.20) 5.3 (0.60)/5.2 (0.60) — Sorbs 254/376 46.6 (16.2)/46.4 (15.8) 26.90 (3.60)/26.7 (5.50) 5.35 (0.37)/5.36 (0.38) 5.47 (0.49)/5.21 (0.57) SardiNIA stage2 555/890 46.4 (15.1)/46.3 (15.8) 26.36 (3.48)/24.61 (4.60) 5.45 (0.85)/5.31 (0.86) — Segovia 274/309 53 (12)/55 (12) 27.35 (3.15)/27.41 (4.68) 5.17(0.49)/5.17 (0.45) — -
Data are mean (SD). Fifteen cohorts were included in the fasting-glucose adjusted analysis shown in Table 2 (ARIC, BLSA, CROATIA, Fenland, FHS, DESIR, GENOMEUTWIN, Lolipop, NTR, ORCADES, SardiNIA, KORA F4, DGI, Sorbs and Health2000). BLSA, DGI, Fenland, FHS, KORA F4 and Sorbs were used for analyses that included 2-h glucose. The mean (mmol/l), SE and N for 2-h glucose levels for males and females, respectively, were: 6.96 (2.47) (236)/6.42 (2.04) (207) in BLSA; 5.75 (1.20) (209)/6.15 (1.25) (254) in DGI; 5.27 (1.41) (600)/5.16 (1.35) (757) in Fenland, 5.744 (1.614) (858)/5.992 (1.707) (1,067) in FHS, and 5.19 (2.02) (254)/5.54 (1.96) (376) in Sorbs. Fasting glucose was not available in KORA S4, thus conditional models were run in KORA F4, a follow-up visit of KORA S4 samples. Mean and SE 2-h glucose levels in males and females, respectively, were: 5.66 (0.67)/5.60 (0.57) for HbA1C and 5.82 (1.20)/5.40 (1.01) for glucose. Cohorts in italics provided only de novo genotyping data). The means for Hb (g/l, males/females) were 148.39 (10.29)/135.94 (9.55) (KORA F3), 148.21 (10.00)/134.51 (9.15) (KORA F4), 152.38 (11.33)/136.56 (10.38) (NHANES III) and 148.54 (12.12)/130.83 (11.60) (SardiNIA). The means for MCV (pg, males/females) were 92.32 (3.91)/90.74 (4.08) (KORA F3), 92.04 (4.23)/90.83 (4.38) (KORA F4), 89.69 (4.45)/89.40 (4.34) (NHANES III) and 87.29 (9.28)/85.64 (9.22) (SardiNIA). The means for MCH (fl, males/females) were 31.22 (1.51)/30.60 (1.64) (KORA F3), 31.50 (1.62)/30.89 (1.73) (KORA F4), 30.50 (1.74)/30.22 (1.67) (NHANES III) and 29.14 (3.60)/28.40 (3.69) (SardiNIA). The means for Iron (ìmol/l, males/females) were 17.66 (5.34)/16.29 (5.25) (KORA F3), 22.41 (6.87)/20.53 (6.53) (KORA F4), 18.78 (6.53)/17.03 (6.96) (NHANES III) and 18.01 (6.23)/15.30 (5.98) (SardiNIA). The means for Transferrin (g/l, males/females) were 2.45 (0.33)/2.56 (0.36) (KORA F3), 2.51 (0.35)/2.54 ( 0.38) (KORA F4), n.a. (NHANES III) and 1.96 (0.52)/2.07 (0.579) (SardiNIA).
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- TABLE 2
Associations with HbA1C of 10 independent loci identified in the meta-analysis
SNP Chr Pos (B36) Nearest locus Effect/other allele CEU freq (effect) HbA1C (%) association Heterogeneity Freq (effect) N β (SE) P χ2P value Q P I2 (%) rs2779116 1 156,852,039 SPTA1 T/C 0.32 0.27 34,663 0.024 (0.004) 2.75 × 10−9 0.673 0.606 0 rs552976 2 169,616,945 G6PC2/ABCB11 G/A 0.66 0.64 40,420* 0.047 (0.003) 8.16 × 10−18 0.596 0.591 0 rs1800562 6 26,201,120 HFE G/A 0.96 0.94 43,778* 0.063 (0.007) 2.59 × 10−20 0.661 0.300 11 rs1799884 7 44,002,308 GCK T/C 0.20 0.18 45,591* 0.038 (0.004) 1.45 × 10−20 0.187 0.120 24 rs6474359 8 41,668,351 ANK1 T/C 0.97 0.97 29,997 0.058 (0.011) 1.18 × 10−8 0.328 0.267 15 rs4737009 8 41,749,562 ANK1 A/G 0.28 0.24 36,862 0.027 (0.004) 6.11 × 10−12 0.182 0.182 21 rs16926246 10 70,763,398 HK1 C/T 0.89 0.90 42,707* 0.089 (0.004) 3.11 × 10−54 0.329 0.162 21 rs1387153 11 92,313,476 MTNR1B T/C 0.28 0.28 32,293 0.028 (0.004) 3.96 × 10−11 0.867 0.857 0 rs7998202 13 112,379,869 ATP11A/TUBGCP3 G/A 0.15 0.14 34,724 0.031 (0.005) 5.24 × 10−9 0.415 0.383 6 rs1046896 17 78,278,822 FN3K T/C 0.25 0.31 45,953* 0.035 (0.003) 1.57 × 10−26 0.450 0.440 2 rs855791 22 35,792,882 TMPRSS6 A/G 0.39 0.42 34,562 0.027 (0.004) 2.74 × 10−14 0.970 0.962 0 -
*Indicates SNPs for which additional de novo genotyping was performed in eight cohorts. The β coefficient denotes the per-effect allele increase in HbA1C (%) at that locus.
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- TABLE 3
Associations with HbA1C of 10 independent loci conditioned on levels of fasting or 2-h glucose
SNP Nearest locus Effect/Other Fasting glucose 2-h glucose HbA1C (%) adjusted for sex, age HbA1C (%) adjusted for glucose, sex, age Fasting glucose (mmol/l) adjusted for sex, age HbA1C (%) adjusted for sex. age HbA1C (%) adjusted for 2 h-glucose, sex, age 2-h glucose (mmol/l) adjusted for sex, age rs2779116 SPTA1 T/C β (SE) 0.019 (0.004) 0.017 (0.004) −0.001 (0.005) 0.026 (0.008) 0.029 (0.008) 0.029 (0.037) P 2.4 × 10−6 1.7 × 10−6 0.900 9.6 × 10−4 2.9 × 10−4 0.432 N 20,700 21,359 21,505 6,394 6,347 6,347 rs552976 G6PC2 /ABCB11 G/A β (SE) 0.028 (0.004) 0.013 (0.003) 0.060 (0.005) 0.029 (0.007) 0.027 (0.007) −0.021 (0.034) P 4.5 × 10−15 2.0 × 10−5 6.3 × 10−36 6.1 × 10−5 1.4 × 10−4 0.538 N 23,496 23,496 23,642 6,393 6,346 6,346 rs1800562 HFE G/A β (SE) 0.054 (0.007) 0.048 (0.006) −0.008 (0.010) 0.095 (0.016) 0.096 (0.016) 0.086 (0.073) P 3.1 × 10−13 2.5 × 10−14 0.419 1.1 × 10−9 1.1 × 10−9 0.239 N 23,503 23,503 23,649 6,389 6,342 6,342 rs1799884 GCK T/C β (SE) 0.030 (0.005) 0.018 (0.004) 0.053 (0.0063) 0.037 (0.010) 0.039 (0.010) 0.111 (0.046) P 5.6 × 10−11 7.3 × 10−6 4.7 × 10−17 1.3 × 10−4 6.2 × 10−5 0.0143 N 23,497 23,497 23,643 6,394 6,347 6,347 rs4737009 ANK1 A/G β (SE) 0.023 (0.004) 0.017 (0.004) 0.010 (0.006) 0.023 (0.008) 0.025 (0.008) −0.049 (0.038) P 3.2 × 10−8 2.7 × 10−6 0.072 4.4 × 10−3 2.3 × 10−3 0.197 N 21,355 21,355 21,501 6,390 6,343 6,343 rs16926246 HK1 C/T β (SE) 0.073 (0.007) 0.069 (0.006) −0.013 (0.009) 0.010 (0.017) 0.097 (0.017) 0.012 (0.092) P 4.8 × 10−26 6.4 × 10−30 0.178 1.6 × 10−9 1.3 × 10−8 0.899 N 22,404 22,404 22,550 5,301 5,254 5,254 rs1387153 MTNR1B T/C β (SE) 0.027 (0.004) 0.013 (0.004) 0.056 (0.006) 0.035 (0.008) 0.032 (0.009) 0.036 (0.040) P 1.9 × 10−11 2.2 × 10−4 1.8 × 10−23 3.1 × 10−5 1.5 × 10−4 0.362 N 20,162 20,162 20,308 6,394 6,347 6,347 rs7998202 ATP11A/TUBGCP3 G/A β (SE) 0.027 (0.006) 0.023 (0.005) 0.013 (0.008) 0.041 (0.012) 0.035 (0.012) −0.035 (0.054) P 3.4 × 10−6 1.3 × 10−5 0.108 4.0 × 10−4 2.6 × 10−3 0.512 N 21,359 21,359 21,505 6,394 6,347 6,347 rs1046896 FN3K T/C β (SE) 0.030 (0.004) 0.026 (0.003) 0.005 (0.005) 0.045 (0.008) 0.043 (0.008) −0.011 (0.036) P 2.0 × 10−16 1.0 × 10−15 0.343 3.0 × 10−9 2.0 × 10−8 0.753 N 23,496 23,496 23,642 6,393 6,346 6,346 rs855791 TMPRSS6 A/G β (SE) 0.020 (0.004) 0.019 (0.003) −0.006 (0.005) 0.024 (0.008) 0.022 (0.008) 0.009 (0.036) P 6.7 × 10−8 8.3 × 10−9 0.223 1.7 × 10−3 6.1 × 10−3 0.815 N 23,508 23,508 23,654 6,394 6,347 6,347 -
β (SE) is the per-effect allele increase in HbA1C (%) as in Table 2. For analyses conditional on fasting glucose, data were available for up to 23,654 samples from 15 cohorts (ARIC, BLSA, CROATIA, Fenland, FHS, DESIR, GENOMEUTWIN, Lolipop, NTR, ORCADES, SardiNIA, KORA F4, DGI, Sorbs and Health2000). For analyses conditional on 2-h glucose, data were available for only a smaller set of six cohorts totaling up to 6,394 samples (BLSA, Fenland, FHS, KORA F4, DGI and Sorbs). The SNP association with HbA1C after adjusting for fasting glucose is attenuated most at the G6PC2/ABCB11, GCK and MTNR1B loci. Associations at ANK1 are given for rs4737009, with the ANK1 SNP showing the strongest association with HbA1C.
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