Table 1 Genome-wide association studies showing the association of SNPs with vitamin B12 concentrations. Genome-wide association studies testing the association between SNPs and vitamin B12 concentrations. The chromosome location, gene name, reference SNP cluster ID, sample size and ethnicity, mean age, observed frequency of the minor allele in the population, effect size and P value are shown in the table. The order of SNPs reflects the order of the chromosome location
From: An update on vitamin B12-related gene polymorphisms and B12 status
Chromosome location | Gene name (gene symbol) | Reference SNP cluster ID | Sample size and ethnicity | Age (years) | Minor allele + minor allele frequency | Effect size | P value | References |
|---|---|---|---|---|---|---|---|---|
1p34.1 | Methylmalonic aciduria and homocystinuria type C protein (MMACHC) | rs12272669 | Icelandic sample: n = 37,283 | 63 ± 24 | A = 0.002 | Effect: A allele Other: G allele β = 0.51 pmol/l | 3.00 × 10−9 | Grarup et al. [12] |
1q42.2 | Intergenic | rs583228 | Initial sample: n = 1999 Chinese Han men | 38 ± 11 | T = 0.220 | Effect: T allele Other: C allele β = not available | 7.68 × 10−6 | Lin et al. [19] |
Replication sample: n = 1496 Chinese men | 37 ± 11 | Effect: T allele Other: C allele β = not available | > 0.05 | |||||
Combined total: n = 3495 |  | Effect: T allele Other: C allele β = 25.50 pg/ml SE = 7.19 | 3.92 × 10−4 | |||||
2q34 | Carbamoyl-phosphate synthase 1 (CPS1) | rs1047891 | Icelandic sample: n = 37,283 | 63 ± 24 | A = 0.372 | Effect: C allele Other: A allele β = 0.04 pmol/l | 7.60 × 10−6 | Grarup et al. [12] |
Danish Inter99 population: n = 5481 | 46 ± 8 | Effect: C allele Other: A allele β = 0.10 pmol/l | 5.50 × 10−4 | |||||
Danish Health 2006: n = 2812 | 49 ± 13 | Effect: C allele Other: A allele β = 0.03 pmol/l | > 0.05 | |||||
Combined total: n = 45,574 |  | Effect: C allele Other: A allele β = not available | 3.00 × 10−8 | |||||
4q31.21 | Methylmalonic aciduria (cobalamin deficiency) cblA type (MMAA) | rs2270655 | Parents of PMNS cohort*: n = 1001 Indian | 36 ± 5 | C = 0.157# | Effect allele: C β = − 0.07 pmol/l | > 0.05 | Nongmaithem et al. [22] |
adults: n = 724 Indian | 38 ± 11 | Effect allele: C β = 0.00 pmol/l | > 0.05 | |||||
PMNS children*: n = 690 Indian | 11 ± 1 | Effect allele: C β = − 0.09 pmol/l | > 0.05 | |||||
PS children†: n = 534 Indian | 5 ± 0 | Effect allele: C β = − 0.20 pmol/l | 2.00 × 10−2 | |||||
4q31.21 | Methylmalonic aciduria (cobalamin deficiency) cblA type (MMAA) | rs2270655 | Icelandic sample: n = 37,283 | 63 ± 24 | C = 0.059 | Effect: G allele Other: C allele β = 0.07 pmol/l | 3.50 × 10−5 | Grarup et al. [12] |
Danish Inter99 population: n = 5481 | 46 ± 8 | Effect: G allele Other: C allele β = 0.30 pmol/l | 2.80 × 10−7 | |||||
Danish Health 2006: n = 2812 | 49 ± 13 | Effect: G allele Other: C allele β = 0.25 pmol/l | 5.80 × 10−8 | |||||
Combined total: n = 45,576 |  | Effect: G allele Other: C allele β = not available | 2.20 × 10−13 | |||||
4q31.21 | Methylmalonic aciduria (cobalamin deficiency) cblA type (MMAA) | rs114699496 | Icelandic sample: n = 25,960 | 63 ± 24 | T = 0.046** | Effect: T Other: C β = − 0.07 pmol/l | 7.60 × 10−6 | Grarup et al. [12] |
5q32 | Intergenic | rs10515552 | Initial sample: n = 1999 Chinese Han men | 38 ± 11 | C = 0.162 | Effect: C allele Other: T allele β = not available | 8.52 × 10−7 | Lin et al. [19] |
Replication sample: n = 1496 Chinese men | 37 ± 11 | Effect: C allele Other: T allele β = not available | 5.15 × 10−3 | |||||
Combined total: n = 3495 |  | Effect: C allele Other: T allele β = 43.93 pg/ml SE = 7.98 | 3.94 × 10−8 | |||||
6p12.3 | Methylmalonyl-CoA Mutase (MUT) | chr6:49,508,102 | Icelandic sample: n = 25,960 | 63 ± 24 | Not available | Effect: C allele Other: G allele β = 0.07 pmol/l | 1.60 × 10−18 | Grarup et al. [12] |
6p12.3 | Methylmalonyl-CoA Mutase (MUT) | rs1141321 (rs9473558) | Icelandic sample: n = 37,283 | 63 ± 24 | T = 0.373 | Effect: C allele Other: T allele β = 0.06 pmol/l | 1.40 × 10−16 | Grarup et al. [12] |
Danish Inter99 population: n = 5481 | 46 ± 8 | Effect: C allele Other: T allele β = 0.12 pmol/l | 1.40 × 10−5 | |||||
Danish Health 2006: n = 2812 | 49 ± 13 | Effect: C allele Other: T allele β = 0.11 pmol/l | 1.40 × 10−7 | |||||
Combined total: n = 45,574 |  | Effect: C allele Other: T allele β = not available | 3.60 × 10−26 | |||||
6p12.3 | Methylmalonyl-CoA mutase (MUT) | rs1141321 (rs9473558) | Initial sample: n = 1999 Chinese Han men | 38 ± 11 | T = 0.237 | Effect: T allele Other: C allele β = − 30.34 pg/ml SE = 8.91 | 5.51 × 10−4 | Lin et al. [19] |
6p12.3 | Methylmalonyl-CoA mutase (MUT) | rs1141321 (rs9473558) | NHS-CGEMS‡: n = 1658 Caucasian women | 59 ± 6 | T = 0.350 | Effect: T allele Other: C allele β = − 0.03 pg/ml SE = 0.01 | 4.27 × 10−2 | Hazra et al. [20] |
SHARe§: n = 1647 Caucasian women | 59 ± 10 | Effect: T allele Other: C allele β = − 0.03 pg/ml SE = 0.01 | 1.87 × 10−2 | |||||
SHARe§: n = 1458 Caucasian men | 59 ± 10 | Effect: T allele Other: C allele β = − 0.07 pg/ml SE = 0.01 | 3.96 × 10−7 | |||||
Combined total: n = 4763 |  | Effect: T allele Other: C allele β = − 0.04 pg/ml SE = 0.01 | 4.05 × 10−8 | |||||
6p12.3 | Methylmalonyl-CoA mutase (MUT) | rs9473555 | Icelandic sample: n = 25,960 | 63 ± 24 | C = 0.402 | Effect: C allele Other: G allele β = − 0.06 pmol/l | 5.40 × 10−17 | Grarup et al. [12] |
6p12.3 | Methylmalonyl-CoA mutase (MUT) | rs9473555 | Initial sample: n = 1999 Chinese Han men | 38 ± 11 | C = 0.238 | Effect: C allele Other: G allele β = − 31.00 pg/ml SE = 8.860 | 4.06 × 10−4 | Lin et al. [19] |
6p12.3 | Methylmalonyl-CoA mutase (MUT) | rs9473555 | NHS-CGEMS‡: n = 1658 Caucasian women | 59 ± 6 | C = 0.350 | Effect: C allele Other: G allele β = − 0.03 pg/ml SE = 0.01 | 4.27 × 10−2 | Hazra et al. [20] |
SHARe§: n = 1647 Caucasian women | 59 ± 10 | Effect: C allele Other: G allele β = − 0.03 pg/ml SE = 0.01 | 2.26 × 10−2 | |||||
SHARe§: n = 1458 Caucasian men | 59 ± 10 | Effect: C allele Other: G allele β = − 0.07 pg/ml SE = 0.01 | 3.71 × 10−7 | |||||
Combined total: n = 4763 |  | Effect: C allele Other: G allele β = − 0.04 pg/ml SE = 0.01 | 4.91 × 10−8 | |||||
6q15 | Nearest gene: sperm acrosome associated 1 (SPACA1) | Chr6_88,792,234 | Icelandic sample: n = 37,283 | 63 ± 24 | G = 0.006 | Effect: G allele Other: A allele β = 0.26 pmol/l | 2.80 × 10−7 | Grarup et al. [12] |
7q21.3 | Paraoxonase 1 (PON1) | rs3917577 | n = 3114 Canadian (85% Causasian, 15% non-Caucasian) | 20–79 (range) | G = 0.020 | Effect:A allele Other: G allele Vitamin B-12 below adequate (< 220 pmol/l): OR 0.67 (95% CI 0.54, 0.81) pmol/l | 7.20 × 10−5 | Zinck et al. [18] |
8q21.13 | Nearest gene: zinc finger and BTB domain containing 10 (ZBTB10) | rs62515066 | Icelandic sample: n = 37,283 | 63 ± 24 | G = 0.025 | Effect: G allele Other: A allele β = 0.12 pmol/l | 5.40 × 10−7 | Grarup et al. [12] |
9p21.1 | None (Intergenic) | rs12377462 | Initial sample: n = 1999 Chinese Han men | 38 ± 11 | T = 0.366 | Effect: T allele Other: C allele β = not available | 3.34 × 10−7 | Lin et al. [19] |
Replication sample: n = 1496 Chinese men | 37 ± 11 | Effect: T allele Other: C allele β = not available | > 0.05 | |||||
Combined total: n = 3495 |  | Effect: T allele Other: C allele β = 28.53 pg/ml SE = 5.99 | 2.02 × 10−6 | |||||
10p12.31 | Cubulin (CUBN) | rs1801222 | n = 3114 Canadian (85% Causasian, 15% non-Caucasian) | 20–79 (range) | A = 0.100 | Effect: G allele Other: A allele Vitamin B12 deficiency (<  148 pmol/l): OR 1.61 (95% CI 1.24, 2.09) pmol/l | 3.00 × 10−4 | Zinck et al. [18] |
10p12.31 | Cubulin (CUBN) | rs1801222 | n = 3114 Canadian (85% Causasian, 15% non-Caucasian) | 20–79 (range) | A = 0.100 | Effect: G allele Other: A allele Vitamin B-12 below adequate (< 220 pmol/l): OR 1.39 (95% CI 1.23, 1.58) pmol/l | 2.00 × 10−7 | Zinck et al. [18] |
10p12.31 | Cubulin (CUBN) | rs1801222 | Icelandic sample: n = 37,283 | 63 ± 24 | A = 0.407 | Effect: G allele Other: A allele β = 0.10 pmol/l | 1.10 × 10−52 | Grarup et al. [12] |
Danish Inter99 population: n = 5481 | 46 ± 8 | Effect: G allele Other: A allele β = 0.14 pmol/l | 7.60 × 10−8 | |||||
Danish Health 2006: n = 2812 | 49 ± 13 | Effect: G allele Other: A allele β = 0.17 pmol/l | 2.90 × 10−18 | |||||
Combined total: n = 45,576 |  | Effect: G allele Other: A allele β = not available | 3.30 × 10−75 | |||||
10p12.31 | Cubulin (CUBN) | rs1801222 | NHS-CGEMS‡: n = 1658 Caucasian women | 59 ± 6 | A = 0.280 | Effect: A allele Other: G allele β = − 0.05 pg/ml SE = 0.01 | 9.04 × 10−5 | Hazra et al. [20] |
SHARe§: n = 1647 Caucasian women | 59 ± 10 | Effect: A allele Other: G allele β = − 0.04 pg/ml SE = 0.02 | 6.32 × 10−3 | |||||
SHARe§: n = 1458 Caucasian men | 59 ± 10 | Effect: A allele Other: G allele β = − 0.05 pg/ml SE = 0.02 | 3.56 × 10−4 | |||||
Combined total: n = 4763 |  | Effect: A allele Other: G allele β = − 0.05 pg/ml SE = 0.01 | 2.87 × 10−9 | |||||
10p12.31 | Cubulin (CUBN) | rs4748353 | n = 3114 Canadian (85% Causasian, 15% non-Caucasian) | 20–79 (range) | C = 0.000 | Effect: C allele Other: T allele Vitamin B12 deficiency (< 148 pmol/l): OR 2.14 (95% CI 1.36, 3.37) pmol/l | 8.00 × 10−4 | Zinck et al. [18] |
10p12.31 | Cubulin (CUBN) | rs11254363 | n = 3114 Canadian (85% Causasian, 15% non-Caucasian) | 20 – 79 (range) | G = 0.010 | Effect: A allele Other: G allele Vitamin B-12 below adequate (< 220 pmol/l): OR 0.81 (95% CI 0.70, 0.93) pmol/l | 3.00 × 10−3 | Zinck et al. [18] |
10p12.31 | Cubulin (CUBN) | rs11254363 | GWAS Meta-analysis: InCHIANTI study: n = 1175 Italian SardiNIA study: n = 1115 Italian BLSA study¶: n = 640 Residents from the USA | InCHIANTI: 68 ± 16 SardiNIA: 45 ± 18 BLSAg: 68 ± 16 | G = 0.300 | Effect: A allele Other: G allele β = − 39.16 pg/ml SE = 9.18 | 7.24 × 10−8 | Tanaka et al. [21] |
Replication study: Progetto Nutrizione study: n = 687 Italian | 47 ± 13 | Effect: A allele Other: G allele β = 3.62 pg/ml SE = 10.94 | > 0.05 | |||||
Combined meta-analysis (GWAS Meta-analysis + Replication study): n = 3613 |  | Effect: A allele Other: G allele β = − 21.49 pg/ml SE = 7.03 | 1.11 × 10−6 | |||||
10p12.31 | Cubulin (CUBN) | rs12243895 | Initial sample: n = 1999 Chinese Han men | 38 ± 11 | A = 0.243 | Effect: A allele Other: G allele β = 23.49 pg/ml SE = 9.06 | 7.11 × 10−3 | Lin et al. [19] |
10p12.31 | Cubulin (CUBN) | rs12780845 | Parents of PMNS cohort*: n = 1001 Indian | 36 ± 5 | G = 0.415# | Effect allele: G β = 0.09 pmol/l | > 0.05 | Nongmaithem et al. [22] |
Adults: n = 724 Indian | 38 ± 11 | Effect allele: G β = 0.09 pmol/l | > 0.05 | |||||
PMNS children*: n = 690 Indian | 11 ± 1 | Effect allele: G β = 0.08 pmol/l | > 0.05 | |||||
PS children†: n = 534 Indian | 5 ± 0 | Effect allele: G β = 0.03 pmol/l | > 0.05 | |||||
10p13 | DNA methyltransferase gene (DNMT2)/TRNA aspartic acid methyltransferase 1 (TRDMT1) | rs2295809 | n = 3114 Canadian (85% Causasian, 15% non-Caucasian) | 20–79 (range) | T = 0.240 | Effect: A allele Other: T allele Vitamin B-12 below adequate (< 220 pmol/l): OR 0.82 (95% CI 0.73, 0.92) pmol/l | 1.00 × 10−3 | Zinck et al. [18] |
10p13 | DNA methyltransferase gene (DNMT2)/TRNA aspartic acid methyltransferase 1 (TRDMT1) | rs56077122 | Icelandic sample: n = 25,960 | 63 ± 24 | A = 0.335 | Effect: A allele Other: C allele β = 0.09 pmol/l | 4.80 × 10−21 | Grarup et al. [12] |
11q12.1 | Intergenic Nearest gene: transcobalamin 1 (TCN1) | rs117456053 | Icelandic sample: n = 25,960 | 63 ± 24 | A = 0.024 | Effect: G allele Other: A allele β = 0.16 pmol/l | 1.90 × 10−9 | Grarup et al. [12] |
11q12.1 | Membrane Spanning 4-Domains A3 (MS4A3) | rs2298585 | Icelandic sample: n = 25,960 | 63 ± 24 | T = 0.001 | Effect: T allele Other: C allele β = 0.21 pmol/l | > 0.05 | Grarup et al. [12] |
11q12.1 | Membrane Spanning 4-Domains A3 (MS4A3) | rs2298585 | Initial sample: n = 1999 Chinese Han men | 38 ± 11 | T = 0.120 | Effect: T allele Other: C allele β = not available | 1.71 × 10−10 | Lin et al. [19] |
Replication sample: n = 1496 Chinese men | 37 ± 11 | Effect: T allele Other: C allele β = not available | 1.58 × 10−6 | |||||
Combined total: n = 3495 |  | Effect: T allele Other: C allele β = 71.80 pg/ml SE = 9.04 | 2.64 × 10−15 | |||||
11q12.1 | Transcobalamin 1 (TCN1) | rs526934 | Adults: n = 724 Indian | 38 ± 11 | G = 0.216# | Effect allele: G β = − 0.07 pmol/l | > 0.05 | Nongmaithem et al. [22] |
PMNS children*: n = 690 Indian | 11 ± 1 | Effect allele: G β = − 0.10 pmol/l | > 0.05 | |||||
PS children†: n = 534 Indian | 5 ± 0 | Effect allele: G β = − 0.16 pmol/l | 2.00 × 10−2 | |||||
11q12.1 | Transcobalamin 1 (TCN1) | rs526934 | n = 3114 Canadian (85% Causasian, 15% non-Caucasian) | 20–79 (range) | G = 0.080 | Effect: A allele Other: G allele Vitamin B-12 below adequate (< 220 pmol/l): OR 1.38 (95% CI 1.21, 1.57) pmol/l | 1.40 × 10−6 | Zinck et al. [18] |
11q12.1 | Transcobalamin 1 (TCN1) | rs526934 | Icelandic sample: n = 25,960 | 63 ± 24 | G = 0.296 | Effect: G allele Other: A allele β = − 0.12 pmol/l | 2.30 × 10−48 | Grarup et al. [12] |
11q12.1 | Transcobalamin 1 (TCN1) | rs526934 | Initial sample: n = 1999 Chinese Han men | 8 ± 11 | G = 0.189 | Effect: G allele Other: A allele β = − 30.39 pg/ml SE = 9.66 | 1.78 × 10−3 | Lin et al. [19] |
11q12.1 | Transcobalamin 1 (TCN1) | rs526934 | NHS-CGEMS‡: n = 1658 Caucasian women | 59 ± 6 | G = 0.270 | Effect: G allele Other: A allele β = − 0.05 pg/ml SE = 0.01 | 1.27 × 10−3 | Hazra et al. [20] |
SHARe§: n = 1647 Caucasian women | 59 ± 10 | Effect: G allele Other: A allele β = − 0.06 pg/ml SE = 0.02 | 6.69 × 10−5 | |||||
SHARe§: n = 1458 Caucasian men | 59 ± 10 | Effect: G allele Other: A allele β = − 0.06 pg/ml SE = 0.02 | 1.64 × 10−4 | |||||
Combined total: n = 4763 |  | Effect: G allele Other: A allele β = − 0.05 pg/ml SE = 0.01 | 2.25 × 10−10 | |||||
11q12.1 | Transcobalamin 1 (TCN1) | rs526934 | GWAS Meta-analysis: InCHIANTI study: n = 1175 Italian SardiNIA study: n = 1115 Italian BLSA study¶: n = 640 Residents from the USA | InCHIANTI: 68 ± 16 SardiNIA: 45 ± 18 BLSAg: 68 ± 16 | G = 0.330 | Effect: A allele Other: G allele β = 36.76 pg/ml SE = 10.35 | 8.33 × 10−7 | Tanaka et al. [21] |
Replication study: Progetto Nutrizione study: n = 687 Italian | 47 ± 14 | Effect: A allele Other: G allele β = 12.83 pg/ml SE = 13.24 | > 0.05 | |||||
Combined meta-analysis (GWAS Meta-analysis + Replication study): n = 3613 |  | Effect: A allele Other: G allele β = 27.62 pg/ml SE = 8.15 | 1.51 × 10−6 | |||||
11q12.1 | Transcobalamin 1 (TCN1) | rs34324219 | Adults: n = 724 Indian | 38 ± 11 | A = 0.041††| Effect allele: A β = − 0.30 pmol/l | 2.00 × 10−2 | Nongmaithem et al. [22] |
PMNS children*: n = 690 Indian | 11 ± 1 | Effect allele: A β = − 0.14 pmol/l | > 0.05 | |||||
PS children†: n = 534 Indian | 5 ± 0 | Effect allele: A β = − 0.65 pmol/l | 9.50 × 10−7 | |||||
11q12.1 | Transcobalamin 1 (TCN1) | rs34324219 | Icelandic sample: n = 37,283 | 63 ± 24 | A = 0.119 | Effect: C allele Other: A allele β = 0.21 pmol/l | 8.80 × 10−71 | Grarup et al. [12] |
Danish Inter99 population: n = 5481 | 46 ± 8 | Effect: C allele Other: A allele β = 0.40 pmol/l | 3.20 × 10−23 | |||||
Danish Health 2006: n = 2812 | 49 ± 13 | Effect: C allele Other: A allele β = 0.30 pmol/l | 3.50 × 10−24 | |||||
Combined total: n = 45,576 |  | Effect: C allele Other: A allele β = not available | 1.10 × 10−111 | |||||
11q12.1 | Transcobalamin 1 (TCN1) | rs34528912 | Adults: n = 724 Indian | 38 ± 11 | T = 0.006††| Effect allele: T β = − 0.79 pmol/l | 1.00 × 10−2 | Nongmaithem et al. [22] |
PMNS children*: n = 690 Indian | 11 ± 1 | Effect allele: T β = 0.38 pmol/l | > 0.05 | |||||
PS children†: n = 534 Indian | 5 ± 0 | Effect allele: T β = − 0.47 pmol/l | 3.00 × 10−2 | |||||
11q12.1 | Transcobalamin 1 (TCN1) | rs34528912 | Icelandic sample: n = 25,960 | 63 ± 24 | T = 0.036 | Effect: T allele Other: C allele β = 0.17 pmol/l | 2.10 × 10−15 | Grarup et al. [12] |
13q32.3 | Citrate Lyase Beta Like (CLYBL) | rs41281112 | Initial sample: n = 1999 Chinese Han men | 38 ± 11 | T = 0.044 | Effect: T allele Other: C allele β = not available | 1.09 × 10−8 | Lin et al. [19] |
Replication sample: n = 1496 Chinese men | 37 ± 11 | Effect: T allele Other: C allele β = not available | 7.41 × 10−3 | |||||
Combined total: n = 3495 |  | Effect: T allele Other: C allele β = − 83.60 pg/ml SE = 13.62 | 9.23 × 10−10 | |||||
13q32.3 | Citrate Lyase Beta Like (CLYBL) | rs41281112 | Icelandic sample: n = 37,283 | 63 ± 24 | T = 0.052 | Effect: C allele Other: T allele β = 0.17 pmol/l | 9.60 × 10−27 | Grarup et al. [12] |
Danish Inter99 population: n = 5481 | 46 ± 8 | Effect: C allele Other: T allele β = 0.24 pmol/l | 1.30 × 10−3 | |||||
Danish Health 2006: n = 2812 | 49 ± 13 | Effect: C allele Other: T allele β = 0.29 pmol/l | 2.50 × 10−7 | |||||
Combined total: n = 45,576 |  | Effect: C allele Other: T allele β = not available | 8.90 × 10−35 | |||||
14q24.3 | ATP Binding Cassette Subfamily D Member 4 (ABCD4) | rs3742801 | Icelandic sample: n = 37,283 | 63 ± 24 | T = 0.294 | Effect: T allele Other: C allele β = 0.05 pmol/l | 5.30 × 10−8 | Grarup et al. [12] |
Danish Inter99 population: n = 5481 | 46 ± 8 | Effect: T allele Other: C allele β = 0.09 pmol/l | 7.60 × 10−4 | |||||
Danish Health 2006: n = 2812 | 49 ± 13 | Effect: T allele Other: C allele β = 0.08 pmol/l | 4.50 × 10−5 | |||||
Combined total: n = 45,571 |  | Effect: T allele Other: C allele β = not available | 1.70 × 10−13 | |||||
14q24.3 | ATP binding cassette subfamily D member 4 (ABCD4) | rs4619337 | Icelandic sample: n = 25,960 | 63 ± 24 | C = 0.292‡‡ | Effect: C allele Other: T allele β = 0.05 pmol/l | 3.40 × 10−8 | Grarup et al. [12] |
19p13.2 | Actin like 9 (ACTL9) | rs2340550 | Initial sample: n = 1999 Chinese Han men | 38 ± 11 | A = 0.134 | Effect: A allele Other: G allele β = not available | 9.34 × 10−7 | Lin et al. [19] |
Replication sample: n = 1496 Chinese men | 37 ± 11 | Effect: A allele Other: G allele β = not available | > 0.05 | |||||
Combined total: n = 3495 |  | Effect: A allele Other: G allele β = 23.39 pg/ml SE = 8.56 | 6.32 × 10−3 | |||||
19p13.2 | CD320 molecule (CD320)/transcobalamin II receptor (TcblR) | rs2336573 | n = 3114 Canadian (85% Causasian, 15% non-Caucasian) | 20–79 (range) | T = 0.010 | Effect: C allele Other: T allele Vitamin B-12 below adequate (< 220 pmol/l): OR 0.62 (95% CI 0.45, 0.86) pmol/l | 3.0 × 10−3 | Zinck et al. [18] |
19p13.2 | CD320 molecule (CD320) / Transcobalamin II Receptor (TcblR) | rs2336573 | Icelandic sample: n = 37,283 | 63 ± 24 | T = 0.031 | Effect: T allele Other: C allele β = 0.32 pmol/l | 1.10 × 10−51 | Grarup et al. [12] |
Danish Inter99 population: n = 5481 | 46 ± 8 | Effect: T allele Other: C allele β = 0.22 pmol/l | 5.70 × 10−3 | |||||
Danish Health 2006: n = 2812 | 49 ± 13 | Effect: T allele Other: C allele β = 0.31 pmol/l | 1.70 × 10−8 | |||||
Combined total: n = 45,575 |  | Effect: T allele Other: C allele β = not available | 8.40 × 10−59 | |||||
19p13.2 | CD320 molecule (CD320) / Transcobalamin II receptor (TcblR) | rs8109720 | Icelandic sample: n = 25,960 | 63 ± 24 | Not available | Effect: G allele Other: A allele β = 0.32 pmol/l | 5.80 × 10−52 | Grarup et al. [12] |
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs281379 | Parents of PMNS cohort*: n = 1001 Indian | 36 ± 5 | A = 0.222# | Effect allele: A β = 0.20 pmol/l | 4.60 × 10−4 | Nongmaithem et al. [22] |
Adults: n = 724 Indian | 38 ± 11 | Effect allele: A β = 0.05 pmol/l | > 0.05 | |||||
PMNS children*: n = 690 Indian | 11 ± 1 | Effect allele: A β = 0.24 pmol/l | 4.50 × 10−4 | |||||
PS children†: n = 534 Indian | 5 ± 0 | Effect allele: A β = 0.13 pmol/l | > 0.05 | |||||
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs492602 | n = 3114 Canadian (85% Causasian, 15% non-Caucasian) | 20–79 (range) | A = 0.210 | Effect: G allele Other: A allele Vitamin B12 deficiency (< 148 pmol/l): OR 0.60 (95% CI 0.54, 0.70) pmol/l | 2.00 × 10−4 | Zinck et al. [18] |
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs492602 | n = 3114 Canadian (85% Causasian, 15% non-Caucasian) | 20–79 (range) | A = 0.210 | Effect: G allele Other: A allele Vitamin B-12 below adequate (< 220 pmol/l): OR 0.71 (95% CI 0.65, 0.81) pmol/l | 9.00 × 10−8 | Zinck et al. [18] |
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs492602 | NHS-CGEMS‡: n = 1658 Caucasian women | 59 ± 6 | G = 0.440 | Effect: G allele Other: A allele β = 0.09 pg/ml SE = 0.01 | 5.39 × 10−11 | Hazra et al. [20] |
SHARe§: n = 1647 Caucasian women | 59 ± 10 | Effect: G allele Other: A allele β = 0.04 pg/ml SE = 0.02 | 5.89 × 10−3 | |||||
SHARe§: n = 1458 Caucasian men | 59 ± 10 | Effect: G allele Other: A allele β = 0.05 pg/ml SE = 0.01 | 2.36 × 10−4 | |||||
Combined total: n = 4763 |  | Effect: G allele Other: A allele β = 0.06 pg/ml SE = 0.01 | 1.30 × 10−14 | |||||
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs492602 | NHS-CGEMS‡: n = 1637 Caucasian women | 59 (Mean) | G = 0.490 | Effect: A allele Other: G allele β = − 0.08 pg/ml SE = 0.01 | 2.68 × 10−10 | Hazra et al. [29] |
Replication: n = 1059 Caucasian women | 63 (Mean) | Effect: A allele Other: G allele β = − 0.10 pg/ml SE = 0.02 | 5.60 × 10−9 | |||||
Combined meta-analysis: n = 2696 |  | Effect: A allele Other: G allele β = − 0.09 pg/ml SE = 0.01 | 5.36 × 10−17 | |||||
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs516316 | Icelandic sample: n = 25,960 | 63 ± 24 | C = 0.469‡‡ | Effect: C allele Other: G allele β = 0.17 pmol/l | 3.60 × 10−103 | Grarup et al. [12] |
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs601338 | Adults: n = 724 Indian | 38 ± 11 | A = 0.230# | Effect: A Other: G β = 0.05 pmol/l | > 0.05 | Nongmaithem et al. [22] |
PMNS children*: n = 690 Indian | 11 ± 1 | Effect: A Other: G β = 0.25 pmol/l | 3.8 × 10−5 | |||||
PS children†: n = 534 Indian | 5 ± 0 | Effect: A Other: G β = 0.18 pmol/l | 4.30 × 10−3 | |||||
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs601338 | n = 25,960 Icelandic | 63 ± 24 | G = 0.384 | Effect: G allele Other: A allele β = − 0.16 pmol/l | 2.40 × 10−95 | Grarup et al. [12] |
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs601338 | NHS-CGEMS‡: n = 1658 Caucasian women | 59 ± 6 | A = 0.450 | Effect: A allele Other: G allele β = 0.09 pg/ml SE = 0.01 | 4.25 × 10−11 | Hazra et al. [20] |
SHARe§: n = 1647 Caucasian women | 59 ± 10 | Effect: A allele Other: G allele β = 0.05 pg/ml SE = 0.01 | 2.63 × 10−3 | |||||
SHARe§: n = 1458 Caucasian men | 59 ± 10 | Effect: A allele Other: G allele β = 0.05 pg/ml SE = 0.01 | 4.02 × 10−4 | |||||
Combined total: n = 4763 |  | Effect: A allele Other: G allele β = 0.06 pg/ml SE = 0.01 | 6.92 × 10−15 | |||||
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs601338 | NHS-CGEMS‡: n = 1658 Caucasian women | 59 (Mean) | G = 0.490 | Effect: G allele Other: A allele β = − 0.08 pg/ml SE = 0.01 | 4.11 × 10−10 | Hazra et al. [29] |
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs602662 | Adults: n = 724 Indian | 38 ± 11 | A = 0.233# | Effect allele: A β = 0.10 pmol/l | > 0.05 | Nongmaithem et al. [22] |
PMNS children*: n = 690 Indian | 11 ± 1 | Effect allele: A β = 0.25 pmol/l | 1.90 × 10−5 | |||||
PS children†: n = 534 Indian | 5 ± 0 | Effect allele: A β = 0.20 pmol/l | 1.40 × 10−3 | |||||
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs602662 | n = 3114 Canadian (85% Causasian, 15% non-Caucasian) | 20–79 (range) | G = 0.230 | Effect: A allele Other: G allele Vitamin B12 deficiency (< 148 pmol/l): OR 0.61 (95% CI 0.47, 0.80) pmol/l | 3.00 × 10−4 | Zinck et al. [18] |
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs602662 | n = 3114 Canadian (85% Causasian, 15% non-Caucasian) | 20–79 (range) | G = 0.230 | Effect: A allele Other: G allele Vitamin B-12 below adequate (< 220 pmol/l): OR 0.74 (95% CI 0.66, 0.84) pmol/l | 1.20 × 10−6 | Zinck et al. [18] |
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs602662 | Icelandic sample: n = 37,283 | 63 ± 24 | G = 0.404 | Effect: A allele Other: G allele β = 0.16 pmol/l | 4.10 × 10−96 | Grarup et al. [12] |
Danish Inter99 population: n = 5481 | 46 ± 8 | Effect: A allele Other: G allele β = 0.19 pmol/l | 3.50 × 10−13 | |||||
Danish - Health 2006: n = 2812 | 49 ± 13 | Effect: A allele Other: G allele β = 0.23 pmol/l | 1.90 × 10−34 | |||||
Combined total n = 45,568 |  | Effect: A allele Other: G allele β = not available | 2.40 × 10−139 | |||||
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs602662 | NHS-CGEMS‡: n = 1658 Caucasian women | 59 ± 6 | G = 0.440 | Effect: G allele Other: A allele β = −  0.08 pg/ml SE = 0.01 | 3.09 × 10−10 | Hazra et al. [20] |
SHARe§: n = 1647 Caucasian women | 59 ± 10 | Effect: G allele Other: A allele β = − 0.05 pg/ml SE = 0.02 | 3.80 × 10−4 | |||||
SHARe§: n = 1458 Caucasian men | 59 ± 10 | Effect: G allele Other: A allele β = −  0.05 pg/ml SE = 0.01 | 2.80 × 10−4 | |||||
Combined total: n = 4763 |  | Effect: G allele Other: A allele β = −  0.07 pg/ml SE = 0.01 | 1.83 × 10−15 | |||||
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs602662 | GWAS Meta-analysis: InCHIANTI study: n = 1175 Italian SardiNIA study: n = 1115 Italian BLSA study¶: n = 640 Residents from the USA | InCHIANTI: 68 ± 16 SardiNIA: 45 ± 18 BLSAg: 68 ± 16 | G = 0.470 | Effect: A allele Other: G allele β = 44.20 pg/ml SE = 8.26 | 2.43 × 10−12 | Tanaka et al. [21] |
Replication study: Progetto Nutrizione study: N = 687 Italian | 47 ± 13 | Effect: A allele Other: G allele β = 58.65 pg/ml SE = 10.43 | 2.19 × 10−10 | |||||
Combined meta-analysis (GWAS Meta-analysis + Replication study): n = 3613 |  | Effect: A allele Other: G allele β = 49.77 pg/ml SE = 6.47 | 2.83 × 10−20 | |||||
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs602662 | NHS-CGEMS‡: n = 1658 Caucasian women | 59 (Mean) | G = 0.490 | Effect: G allele Other: A allele β = − 0.08 pg/ml SE = 0.01 | 6.54 × 10−10 | Hazra et al. [29] |
Replication: n = 1056 Caucasian women | 63 (Mean) |  | Effect: G allele Other: A allele β = − 0.08 pg/ml SE = 0.02 | 1.13 × 10−6 | ||||
Combined meta-analysis: n = 2714 |  |  | Effect: G allele Other: A allele β = − 0.08 pg/ml SE = 0.01 | 3.52 × 10−15 | ||||
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs838133 | Adults: n = 724 Indian | 38 ± 11 | T = 0.205# | Effect allele: A β = 0.05 pmol/l | > 0.05 | Nongmaithem et al. [22] |
PMNS children*: n = 690 Indian | 11 ± 1 | Effect allele: A β = 0.27 pmol/l | 2.00 × 10−4 | |||||
PS children†: n = 534 Indian | 5 ± 0 | Effect allele: A β = 0.06 pmol/l | > 0.05 | |||||
19q13.33 | Fucosyl transferase 2 gene (FUT2) | rs1047781 | Initial sample: n = 1999 Chinese Han men | 38 ± 11 | T = 0.459 | Effect: T allele Other: A allele β = not available | 4.63 × 10−17 | Lin et al. [19] |
Replication sample: n = 1496 Chinese men | 37 ± 11 | Effect: T allele Other: A allele β = not available | 6.79 × 10−22 | |||||
Combined total: n = 3495 |  | Effect: T allele Other: A allele β = 70.21 pg/ml SE = 5.53 | 3.62 × 10−36 | |||||
19p13.3 | Fucosyltransferase 6 (FUT6) | rs708686 | Adults: n = 724 Indian | 38 ± 11 | T = 0.335# | Effect: T allele β = 0.13 pmol/l | 1.0 × 10−2 | Nongmaithem et al. [22] |
PMNS children*: n = 690 Indian | 11 ± 1 | Effect: T allele β = 0.22 pmol/l | 2.20 × 10−4 | |||||
PS children†: n = 534 Indian | 5 ± 0 | Effect: T allele β = 0.23 pmol/l | 2.70 × 10−4 | |||||
19p13.3 | Fucosyltransferase 6 (FUT6) | rs708686 | n = 25,960 Icelandic | 63 ± 24 | T = 0.301‡‡ | Effect: T allele Other: C allele β = 0.05 pmol/l | 2.90 × 10−9 | Grarup et al. [12] |
19p13.3 | Fucosyltransferase 6 / Fucosyltransferase 3 (FUT6/FUT3) | rs3760775 | Parents of PMNS cohort*: n = 1001 Indian | 36 ± 5 | A = 0.188# | Effect allele: A β = 0.24 pmol/l | 6.00 × 10−6 | Nongmaithem et al. [22] |
Adults: n = 724 Indian | 38 ± 11 | Effect allele: A β = 0.24 pmol/l | 9.90 × 10−5 | |||||
PMNS children*: n = 690 Indian | 11 ± 1 | Effect allele: A β = 0.31 pmol/l | 2.90 × 10−6 | |||||
PS children†: n = 534 Indian | 5 ± 0 | Effect allele: A β = 0.24 pmol/l | 2.10 × 10−4 | |||||
19p13.3 | Fucosyltransferase 6 (FUT6) | rs3760776 | Parents of PMNS cohort*: n = 1001 Indian | 36 ± 5 | T = 0.161# | Effect allele: T β = 0.10 pmol/l | > 0.05 | Nongmaithem et al. [22] |
Adults: n = 724 Indian | 38 ± 11 | Effect allele: T β = 0.23 pmol/l | 4.40 × 10−4 | |||||
PMNS children*: n = 690 Indian | 11 ± 1 | Effect allele: T β = 0.30 pmol/l | 3.30 × 10−6 | |||||
PS children†: n = 534 Indian | 5 ± 0 | Effect allele: T β = 0.18 pmol/l | 6.50 × 10−3 | |||||
19p13.3 | Fucosyltransferase 6 (FUT6) | rs3760776 | n = 25,960 Icelandic | 63 ± 24 | A = 0.071 | Effect: A allele Other: G allele β = 0.07 pmol/l | 4.40 × 10−6 | Grarup et al. [12] |
19p13.3 | Fucosyltransferase 6 (FUT6) | rs3760776 | Initial sample: n = 1999 Chinese Han men | 38 ± 11 | A = 0.212 | Effect: A allele Other: G allele β = not available | 4.23 × 10−10 | Lin et al. [19] |
Replication sample: n = 1496 Chinese men | 37 ± 11 | Effect: A allele Other: G allele β = not available | 1.98 × 10−4 | |||||
Combined total: n = 3495 |  | Effect: A allele Other: G allele β = 49.78 pg/ml SE = 6.82 | 3.68 × 10−13 | |||||
19p13.3 | Fucosyltransferase 6 (FUT6) | rs7788053 | Icelandic sample: n = 37,283 | 63 ± 24 | A = 0.254 | Effect: A allele Other: G allele β = 0.05 pmol/l | 2.10 × 10−7 | Grarup et al. [12] |
Danish Inter99 population: n = 5481 | 46 ± 8 | Effect: A allele Other: G allele β = 0.05 pmol/l | > 0.05 | |||||
Danish Health 2006: n = 2812 | 49 ± 13 | Effect: A allele Other: G allele β = 0.07 pmol/l | 7.20 × 10−4 | |||||
Combined total: n = 45,575 |  | Effect: A allele Other: G allele β = not available | 1.70 × 10−10 | |||||
19p13.3 | Fucosyltransferase 6 (FUT6) | rs78060698 | Parents of PMNS cohort*: n = 1001 Indian | 36 ± 5 | A = 0.130††| Effect allele: A β = 0.21 pmol/l | 2.90 × 10−4 | Nongmaithem et al. [22] |
adults: n = 724 Indian | 38 ± 11 | Effect allele: A β = 0.20 pmol/l | 3.70 × 10−3 | |||||
PMNS children*: n = 690 Indian | 11 ± 1 | Effect allele: A β = 0.27 pmol/l | 1.20 × 10−4 | |||||
PS children†: n = 534 Indian | 5 ± 0 | Effect allele: A β = 0.19 pmol/l | 8.20 × 10−3 | |||||
21q22.3 | Cystathionine beta synthase (CBS) | rs2124459 | n = 3114 Canadian (85% Causasian, 15% non-Caucasian) | 20–79 (range) | C = 0.180 | Effect: T allele Other: C allele Vitamin B-12 below adequate (< 220 pmol/l): OR 0.82 (95% CI 0.73, 0.93) pmol/l | 2.00 × 10−3 | Zinck et al. [18] |
22q12.2 | Transcobalamin 2 (TCN2) | rs757874 | n = 3114 Canadian (85% Causasian, 15% non-Caucasian) | 20–79 (range) | T = 0.080 | Effect: G allele Other: T allele Vitamin B-12 below adequate (< 220 pmol/l): OR 1.42 (95% CI 1.11, 1.72) pmol/l | 3.30 × 10−4 | Zinck et al. [18] |
22q12.2 | Transcobalamin 2 (TCN2) | rs1131603 | Adults: n = 724 Indian | 38 ± 11 | C = 0.023# | Effect: C allele β = 0.43 pmol/l | 4.00 × 10−2 | Nongmaithem et al. [22] |
PMNS children*: n = 690 Indian | 11 ± 1 | Effect: C allele β = 0.05 pmol/l | > 0.05 | |||||
PS children†: n = 534 Indian | 5 ± 0 | Effect: C allele β = 0.44 pmol/l | 5.00 × 10−2 | |||||
22q12.2 | Transcobalamin 2 (TCN2) | rs1131603 | Icelandic sample: n = 37,283 | 63 ± 24 | C = 0.055 | Effect: C allele Other: T allele β = 0.19 pmol/l | 4.30 × 10−28 | Grarup et al. [12] |
Danish Inter99 population: n = 5481 | 46 ± 8 | Effect: C allele Other: T allele β = 0.33 pmol/l | 1.80 × 10−9 | |||||
Danish Health 2006: n = 2812 | 49 ± 13 | Effect: C allele Other: T allele β = 0.33 pmol/l | 5.30 × 10−17 | |||||
Combined total: n = 45,575 |  | Effect: C allele Other: T allele β = not available | 4.90 × 10−49 | |||||
22q12.2 | Transcobalamin 2 (TCN2) | rs5753231 | Icelandic sample: n = 25,960 | 63 ± 24 | T = 0.210 | Effect: C allele Other: T allele β = 0.06 pmol/l | 7.50 × 10−10 | Grarup et al. [12] |