Table 2.
Replication of European Metabochip index SNPs for 39 fasting glucose and 17 fasting insulin loci via transethnic meta-analysis
| Locus/gene | Lead EUR | C/NC allele | Coded allele frequency | Effect β of coded allele (SE) | Analyses with p < 0.05 | p value TE Meta (Het.) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| EUR | H/L | AA | ASN | TE Meta | EUR | H/L | AA | ASN | TE Meta | |||||
| Fasting glucose loci (NTE = 26,760, NEUR = 118,881) | ||||||||||||||
| 1q32.3 PROX1 |
rs340874 | A/G | 0.48 | 0.60 | 0.82 | 0.61 | 0.67 | −0.015 (0.002) | −0.004 (0.006) | −0.009 (0.009) | 0.076 (0.027) | −0.003 (0.005) | ASN | 0.59 (0.02) |
| 2p23.3 GCKR |
rs780094 | A/G | 0.39 | 0.35 | 0.19 | 0.52 | 0.30 | −0.029 (0.002) | −0.033 (0.007) | −0.016 (0.010) | −0.051 (0.027) | −0.029 (0.005) | H/L, ASN, TE | 2 × 10−8 (0.2) |
| 2q31.1 G6PC2 |
rs560887 | A/G | 0.30 | 0.17 | 0.07 | 0.03 | 0.14 | −0.075 (0.003) | −0.086 (0.008) | −0.063 (0.014) | −0.065 (0.077) | −0.079 (0.007) | H/L, AA, TE | 1 × 10−29 (0.48) |
| 3q21.1 ADCY5 |
rs11708067 | A/G | 0.79 | 0.75 | 0.84 | 0.96 | 0.78 | 0.024 (0.003) | 0.021 (0.007) | 0.052 (0.010) | −0.254 (0.171) | 0.031 (0.006) | H/L, AA, TE | 5 × 10−8 (0.02) |
| 3q26.2 SLC2A2 |
rs1280 | A/G | 0.86 | 0.84 | 0.65 | 0.97 | 0.73 | 0.031 (0.003) | 0.052 (0.009) | −0.001 (0.007) | 0.043 (0.082) | 0.021 (0.006) | H/L, TE | 1 × 10−4 (2 × 10−5) |
| 7p21.2 DGKB |
rs2191349 | A/C | 0.53 | 0.48 | 0.57 | 0.69 | 0.51 | 0.032 (0.002) | 0.023 (0.006) | 0.005 (0.009) | 0.003 (0.028) | 0.017 (0.005) | H/L, TE | 8 × 10−4 (0.42) |
| 7p13 GCK |
rs730497 | A/G | 0.16 | 0.20 | 0.18 | 0.18 | 0.20 | 0.061 (0.003) | 0.061 (0.008) | 0.056 (0.009) | 0.004 (0.034) | 0.057 (0.006) | H/L, AA, TE | 3 × 10−22 (0.37) |
| 8q24.11 SLC30A8 |
rs11558471 | A/G | 0.68 | 0.75 | 0.90 | 0.57 | 0.77 | 0.032 (0.002) | 0.018 (0.007) | 0.014 (0.012) | −0.004 (0.026) | 0.017 (0.006) | H/L, TE | 4 × 10−3 (0.22) |
| 9p24.2 GLIS3 |
rs10814916 | A/C | 0.49 | 0.43 | 0.33 | 0.54 | 0.40 | −0.017 (0.002) | −0.016 (0.006) | −0.009 (0.008) | −0.066 (0.027) | −0.015 (0.005) | H/L, ASN, TE | 1 × 10−3 (0.21) |
| 10q25.2 ADRA2A |
rs11195502 | A/G | 0.09 | 0.13 | 0.34 | 0.07 | 0.25 | −0.036 (0.004) | −0.014 (0.010) | −0.012 (0.008) | −0.022 (0.054) | −0.013 (0.006) | TE | 0.04 (0.62) |
| 10q25.2 TCF7L2 |
rs4506565 | A/T | 0.70 | 0.71 | 0.56 | 0.93 | 0.64 | −0.024 (0.002) | −0.030 (0.007) | −0.019 (0.007) | −0.137 (0.060) | −0.025 (0.005) | All | 3 × 10−7 (0.19) |
| 11p11.2 CRY2 |
rs11605924 | A/C | 0.49 | 0.54 | 0.86 | 0.81 | 0.63 | 0.022 (0.002) | 0.017 (0.006) | 0.027 (0.011) | −0.066 (0.034) | 0.018 (0.005) | All | 1 × 10−3 (0.03) |
| 11p11.2 MADD |
rs11039182 | A/G | 0.73 | 0.82 | 0.95 | 0.97 | 0.85 | 0.023 (0.003) | 0.000 (0.009) | 0.021 (0.016) | −0.002 (0.091) | 0.004 (0.007) | None | 0.55 (0.67) |
| 11q12.2 FADS2 |
rs174550 | A/G | 0.66 | 0.52 | 0.91 | 0.57 | 0.60 | 0.018 (0.002) | 0.026 (0.007) | 0.036 (0.013) | 0.039 (0.027) | 0.029 (0.006) | H/L, AA, TE | 7 × 10−7 (0.9) |
| 11q14.3 MTNR1B |
rs10830963 | C/G | 0.71 | 0.79 | 0.93 | 0.60 | 0.81 | −0.078 (0.003) | −0.062 (0.008) | −0.090 (0.014) | −0.078 (0.026) | −0.068 (0.006) | All | 7 × 10−27 (0.21) |
| 15q22.2 C2CD4A |
rs4502156 | A/G | 0.55 | 0.40 | 0.26 | 0.52 | 0.35 | 0.023 (0.002) | 0.017 (0.007) | 0.006 (0.008) | 0.008 (0.026) | 0.012 (0.005) | H/L, TE | 0.01 (0.77) |
| 9p21.3 CDKN2B |
rs10811661 | A/G | 0.82 | 0.86 | 0.93 | 0.56 | 0.86 | 0.024 (0.003) | 0.021 (0.009) | 0.017 (0.014) | 0.072 (0.026) | 0.024 (0.007) | H/L, ASN, TE | 0.02 (0.29) |
| 5q15 PCSK1 |
rs4869272 | A/G | 0.69 | 0.75 | 0.78 | 0.73 | 0.76 | 0.018 (0.002) | 0.021 (0.007) | 0.019 (0.008) | 0.032 (0.029) | 0.020 (0.005) | H/L, AA, TE | 1 × 10−3 (0.97) |
| 13q12.2 PDX1 |
rs11619319 | A/G | 0.77 | 0.71 | 0.83 | 0.55 | 0.75 | −0.020 (0.002) | −0.008 (0.007) | −0.017 (0.010) | −0.054 (0.026) | −0.012 (0.006) | AA, ASN, TE | 0.05 (0.32) |
| 8p23.1 PPP1R3B |
rs983309 | A/C | 0.12 | 0.21 | 0.28 | 0.02 | 0.24 | 0.026 (0.003) | 0.023 (0.008) | 0.017 (0.008) | 0.004 (0.104) | 0.020 (0.006) | H/L, AA, TE | 2 × 10−3 (0.96) |
| 7p12.1 GRB10 |
rs6943153 | A/G | 0.34 | 0.45 | 0.68 | 0.28 | 0.54 | 0.015 (0.002) | 0.019 (0.006) | −0.004 (0.008) | −0.010 (0.030) | 0.009 (0.005) | H/L, TE | 0.07 (0.11) |
| 11q13.4 ARAP1 |
rs11603334 | A/G | 0.17 | 0.08 | 0.05 | 0.05 | 0.07 | −0.019 (0.003) | −0.030 (0.011) | −0.039 (0.016) | −0.086 (0.067) | −0.033 (0.009) | H/L, AA, TE | 1 × 10−5 (0.69) |
| 20p11.21 FOXA2 |
rs6113722 | A/G | 0.04 | 0.05 | 0.16 | 0.18 | 0.13 | −0.035 (0.005) | −0.042 (0.014) | −0.040 (0.010) | −0.090 (0.033) | −0.043 (0.008) | All | 2 × 10−6 (0.55) |
| 9q31.3 IKBKAP |
rs16913693 | A/C | 0.97 | 0.96 | 0.77 | 1 | 0.81 | 0.043 (0.007) | 0.010 (0.017) | −0.012 (0.008) | 0.334 (0.333) | −0.008 (0.008) | None | 0.51 (0.48) |
| 9q34.3 DNLZ |
rs3829109 | A/G | 0.29 | 0.33 | 0.17 | 0.13 | 0.28 | −0.017 (0.003) | −0.021 (0.007) | −0.026 (0.010) | 0.000 (0.040) | −0.022 (0.006) | H/L, AA, TE | 5 × 10−4 (0.91) |
| 14q32.2 WARS |
rs3783347 | A/C | 0.21 | 0.12 | 0.06 | 0.1 | 0.11 | −0.017 (0.003) | −0.023 (0.010) | 0.000 (0.014) | 0.000 (0.044) | −0.014 (0.008) | H/L | 0.08 (0.40) |
| 19q13.32 GIPR |
rs2302593 | C/G | 0.5 | 0.51 | 0.28 | 0.39 | 0.42 | 0.014 (0.002) | −0.013 (0.006) | −0.002 (0.008) | 0.019 (0.027) | −0.008 (0.005) | H/L | 0.05 (0.55) |
| 6p22.3 CDKAL1 |
rs9368222 | A/C | 0.28 | 0.23 | 0.19 | 0.41 | 0.23 | 0.014 (0.002) | 0.025 (0.007) | 0.025 (0.009) | 0.041 (0.026) | 0.026 (0.006) | H/L, AA, TE | 3 × 10−5 (0.94) |
| 12q24.33 P2RX2 |
rs10747083 | A/G | 0.66 | 0.69 | 0.85 | 0.83 | 0.74 | 0.013 (0.002) | 0.010 (0.007) | 0.012 (0.011) | −0.017 (0.034) | 0.010 (0.006) | None | 0.12 (0.88) |
| 20q12 TOP1 |
rs6072275 | A/G | 0.16 | 0.12 | 0.08 | 0.02 | 0.11 | 0.016 (0.003) | 0.021 (0.010) | 0.019 (0.013) | −0.075 (0.121) | 0.021 (0.008) | H/L, TE | 5 × 10−3 (0.53) |
| 3q27.2 IGF2BP2 |
rs7651090 | A/G | 0.69 | 0.7 | 0.46 | 0.7 | 0.59 | −0.013 (0.002) | −0.011 (0.007) | −0.011 (0.007) | −0.023 (0.029) | −0.011 (0.005) | TE | 0.07 (0.90) |
| 13q13.1 KL |
rs576674 | A/G | 0.85 | 0.68 | 0.4 | 0.85 | 0.56 | −0.017 (0.003) | −0.026 (0.007) | −0.014 (0.007) | 0.054 (0.038) | −0.019 (0.005) | H/L, AA, TE | 7 × 10−4 (0.08) |
| 3p21.31 AMT |
rs11715915 | A/G | 0.32 | 0.21 | 0.24 | 0.08 | 0.22 | −0.012 (0.002) | −0.007 (0.008) | 0.003 (0.008) | 0.053 (0.051) | −0.002 (0.006) | None | 0.59 (0.56) |
| 6p24.3 RREB1 |
rs17762454 | A/G | 0.26 | 0.33 | 0.16 | 0.41 | 0.28 | 0.012 (0.002) | 0.017 (0.007) | 0.012 (0.010) | 0.011 (0.027) | 0.015 (0.005) | H/L, TE | 0.02 (0.97) |
| 5q13.3 ZBED3 |
rs7708285 | A/G | 0.73 | 0.69 | 0.85 | 0.91 | 0.74 | −0.011 (0.003) | −0.004 (0.007) | 0.003 (0.010) | 0.002 (0.060) | −0.003 (0.006) | None | 0.4 (0.47) |
| 12q13.3 GLS2 |
rs2657879 | A/G | 0.82 | 0.81 | 0.93 | NA | 0.83 | −0.012 (0.003) | −0.011 (0.008) | 0.016 (0.015) | … | −0.005 (0.007) | None | 0.43 (0.11) |
| 2p23.3 DPYSL5 |
rs1371614 | A/G | 0.25 | 0.38 | 0.35 | 0.16 | 0.36 | 0.020 (0.004) | 0.021 (0.007) | −0.006 (0.007) | −0.021 (0.036) | 0.009 (0.005) | H/L | 0.03 (0.05) |
| 15q22.2 C2CD4B |
rs12440695* | A/G | 0.63 | 0.57 | 0.83 | 0.71 | 0.65 | 0.008 (0.003) | 0.004 (0.007) | −0.002 (0.009) | −0.011 (0.028) | 0.003 (0.005) | None | 0.63 (0.58) |
| 11p11.2 OR4S1 |
rs1483121 | A/G | 0.14 | 0.09 | 0.03 | 0.03 | 0.08 | −0.027 (0.005) | 0.008 (0.011) | −0.022 (0.022) | −0.101 (0.220) | 0.002 (0.010) | None | 0.59 (0.62) |
| Fasting insulin loci (NTE = 22,674, NEUR = 99,029) | ||||||||||||||
| 1q41 LYPLAL1 |
rs4846565 | A/G | 0.33 | 0.41 | 0.09 | 0.34 | 0.32 | −0.013 (0.002) | −0.023 (0.008) | −0.007 (0.013) | 0.022 (0.028) | −0.017 (0.007) | H/L, TE | 0.01 (0.34) |
| 2p23.3 GCKR |
rs780094 | A/G | 0.39 | 0.35 | 0.19 | 0.52 | 0.30 | −0.029 (0.002) | −0.031 (0.008) | −0.029 (0.010) | −0.011 (0.027) | −0.030 (0.006) | H/L, AA, TE | 2 × 10−7 (0.41) |
| 2q24.3 GRB14 |
rs10195252 | A/G | 0.60 | 0.67 | 0.28 | 0.89 | 0.49 | 0.017 (0.002) | 0.041 (0.008) | 0.036 (0.008) | −0.044 (0.044) | 0.037 (0.006) | H/L, AA, TE | 1 × 10−10 (0.29) |
| 2q36.3 IRS1 |
rs2943645 | A/G | 0.63 | 0.74 | 0.63 | 0.90 | 0.68 | 0.019 (0.002) | 0.018 (0.009) | 0.012 (0.008) | 0.062 (0.046) | 0.016 (0.006) | H/L, TE | 4 × 10−3 (0.54) |
| 3p25.2 PPARG |
rs17036328 | A/G | 0.86 | 0.89 | 0.83 | 0.95 | 0.85 | 0.021 (0.003) | 0.038 (0.012) | 0.009 (0.010) | 0.036 (0.068) | 0.022 (0.007) | H/L, TE | 2 × 10−3 (0.15) |
| 4q22.1 FAM13A |
rs3822072 | A/G | 0.48 | 0.44 | 0.51 | 0.63 | 0.47 | 0.012 (0.002) | 0.008 (0.008) | 0.018 (0.010) | 0.024 (0.028) | 0.012 (0.006) | AA, TE | 0.04 (0.82) |
| 4q24 TET2 |
rs974801 | A/G | 0.62 | 0.58 | 0.72 | 0.40 | 0.64 | −0.014 (0.002) | −0.018 (0.008) | −0.009 (0.008) | −0.023 (0.027) | −0.015 (0.006) | H/L, TE | 6 × 10−3 (0.31) |
| 4q32.1 PDGFC |
rs6822892 | A/G | 0.68 | 0.59 | 0.27 | 0.70 | 0.45 | 0.014 (0.002) | 0.012 (0.008) | 0.003 (0.008) | 0.009 (0.029) | 0.009 (0.006) | None | 0.12 (0.76) |
| 5q11.2 ARL15 |
rs4865796 | A/G | 0.67 | 0.79 | 0.75 | 0.81 | 0.77 | 0.015 (0.002) | 0.016 (0.009) | 0.024 (0.008) | 0.006 (0.036) | 0.020 (0.006) | AA, TE | 9 × 10−4 (0.80) |
| 5q11.2 ANKRD55 |
rs459193 | A/G | 0.27 | 0.27 | 0.42 | 0.52 | 0.36 | −0.015 (0.002) | −0.025 (0.009) | −0.022 (0.008) | −0.040 (0.026) | −0.022 (0.006) | All | 4 × 10−5 (0.30) |
| 6p21.31 UHRF1BP1 |
rs6912327 | A/G | 0.80 | 0.69 | 0.35 | NA | 0.51 | 0.016 (0.003) | 0.004 (0.008) | −0.004 (0.008) | … | 0.001 (0.006) | None | 0.83 (0.08) |
| 6q22.33 RSPO3 |
rs2745353 | A/G | 0.51 | 0.58 | 0.60 | 0.61 | 0.59 | 0.011 (0.002) | 0.016 (0.008) | 0.010 (0.008) | −0.039 (0.027) | 0.011 (0.005) | H/L, TE | 0.03 (0.25) |
| 7q11.23 HIP1 |
rs1167800 | A/G | 0.54 | 0.67 | 0.84 | 0.69 | 0.73 | 0.011 (0.002) | 0.018 (0.008) | 0.009 (0.010) | −0.004 (0.028) | 0.011 (0.006) | H/L | 0.08 (0.07) |
| 8p23.1 PPP1R3B |
rs983309 | A/C | 0.13 | 0.21 | 0.28 | 0.02 | 0.25 | 0.022 (0.003) | 0.026 (0.010) | 0.024 (0.008) | −0.082 (0.103) | 0.026 (0.006) | All | 2 × 10−5 (0.02) |
| 10q25.2 TCF7L2 |
rs7903146 | A/G | 0.27 | 0.25 | 0.28 | 0.08 | 0.27 | −0.013 (0.002) | −0.014 (0.009) | −0.022 (0.008) | 0.023 (0.057) | −0.019 (0.006) | AA, TE | 1 × 10−3 (0.51) |
| 12q23.2 IGF1 |
rs35767 | A/G | 0.18 | 0.24 | 0.44 | 0.33 | 0.36 | −0.003 (0.003) | −0.014 (0.011) | 0.006 (0.008) | −0.050 (0.032) | −0.004 (0.006) | None | 0.43 (0.28) |
| 19q13.11 PEPD |
rs731839 | A/G | 0.66 | 0.61 | 0.63 | 0.48 | 0.61 | −0.015 (0.002) | −0.016 (0.008) | −0.003 (0.008) | −0.037 (0.026) | −0.012 (0.005) | H/L, TE | 0.03 (0.23) |
EUR, individuals of European descent from Scott et al. [11] genotyped on Metabochip. Models included continuous BMI covariate, *rs12440695 used as a linkage disequilibrium proxy (r 2 = 0.98) for the index SNP rs11071657, which did not pass quality control. β, allelic effect size for an additive genetic model corresponding to the coded (C) allele, is shown in units of mmol/l for fasting glucose and natural log-transformed pmol/l for fasting insulin. Full results for models with and without BMI covariate for fasting glucose and fasting insulin are shown in ESM Table 5 and ESM Table 6, respectively
p values are shown for the transethnic (TE) meta-analysis and heterogeneity (Het.) in effect across populations