Table 1.
Novel loci detected via multivariate GWAS for IgG N-glycosylation phenotypes
| Candidate genes | Phenotypes grouping | Top variant | EA | Discovery: ORCADES | Replication I: KORCULA + VIS | Replication II: TWINSUK | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| β S (s.e.) | P | P MANOVA | β S (s.e.) | P S | r ρ | P MANOVA | β S (s.e.) | P S | r ρ | ||||
| ELL2 | digalactosylation | rs11135441 | T | 0.0336 (0.0056) | 1.6E−09 | 4.5E−04 | 0.0276 (0.0058) | 2.1E−06 | 0.60 | 6.9E−09 | 0.0183 (0.0027) | 5.5E−12 | 0.86 |
| sialylation | rs11135441 | T | 0.0313 (0.0050) | 5.0E−10 | 1.1E−04 | 0.0234 (0.0056) | 2.7E−05 | 0.76 | 3.6E−09 | 0.0091 (0.0014) | 2.7E−10 | 0.96 | |
| HLA-B-C | galactosylation | rs116108880 | G | 0.0408 (0.0066) | 8.3E−10 | 6.2E−01 | 0.0188 (0.0053) | 4.0E−04 | 0.39 | 3.8E−08 | 0.0160 (0.0031) | 2.2E−07 | 0.74 |
| IGH | N-glycosylation | rs35590487 | T | 0.0671 (0.0080) | 6.3E−17 | 2.3E−02 | 0.0218 (0.0074) | 3.1E−03 | 0.10 | 1.0E−31 | 0.0534 (0.0040) | 5.2E−41 | 0.76 |
| monogalactosylation | rs35590487 | T | 0.0465 (0.0055) | 3.6E−17 | 7.1E−02 | 0.0178 (0.0040) | 9.5E−06 | 0.90 | 6.3E−25 | 0.0358 (0.0032) | 1.2E−28 | 0.86 | |
| galactosylation | rs35590487 | T | 0.0637 (0.0073) | 3.4E−18 | 8.8E−02 | 0.0212 (0.0059) | 3.3E−04 | 0.02 | 4.7E−30 | 0.0501 (0.0039) | 4.1E−38 | 0.85 | |
| monosialylation | rs35590487 | T | 0.0325 (0.0046) | 9.9E−13 | 3.5E−01 | 0.0114 (0.0044) | 9.9E−03 | 0.99 | 6.3E−24 | 0.0287 (0.0026) | 1.2E−27 | 0.97 | |
| sialylation | rs35590487 | T | 0.0379 (0.0054) | 1.5E−12 | 3.5E−01 | 0.0113 (0.0050) | 2.3E−02 | 0.36 | 5.9E−23 | 0.0287 (0.0026) | 1.2E−27 | 0.94 | |
| fucosylation | rs58087925 | T | 0.0625 (0.0070) | 3.8E−19 | 7.2E−02 | 0.0242 (0.0059) | 4.5E−05 | 0.18 | 3.7E−34 | 0.0523 (0.0038) | 8.3E−43 | 0.93 | |
| bisecting GlcNAc | rs8013055 | A | 0.0370 (0.0052) | 1.0E−12 | 3.0E−01 | 0.0077 (0.0058) | 1.8E−01 | 0.70 | 1.1E−15 | 0.0261 (0.0029) | 1.9E−19 | 0.96 | |
| AZI1 | N-glycosylation | rs9319617 | C | 0.0453 (0.0076) | 2.5E−09 | 9.7E−03 | 0.0204 (0.0064) | 1.4E−03 | 0.69 | 7.6E−07 | 0.0199 (0.0033) | 2.2E−09 | 0.75 |
| galactosylation | rs9319617 | C | 0.0422 (0.0073) | 2.7E−09 | 2.6E−03 | 0.0189 (0.0047) | 6.2E−-05 | 0.79 | 1.2E−06 | 0.0176 (0.0029) | 8.5E−10 | 0.78 | |
| fucosylation | rs2659009 | A | 0.0414 (0.0063) | 3.9E−11 | 5.1E−04 | 0.0168 (0.0049) | 5.8E−04 | 0.85 | 6.0E−05 | 0.0159 (0.0027) | 4.0E−09 | 0.89 | |
| FUT6-3 | N-glycosylation | rs12019136 | A | 0.0574 (0.0078) | 1.9E−13 | 3.3E−01 | 0.0022 (0.0070) | 7.5E−01 | 0.01 | 3.3E−15 | 0.0251 (0.0031) | 6.3E−16 | 0.82 |
Nine multivariate GWA scans were performed, including one using all the 23 phenotypes, as well as eight different subgroupings according to type of glycosylation. Replication was performed by (i) MANOVA test in the replication cohorts (P MANOVA); and (ii) testing the association between the phenotypic score (constructed based on the coefficients estimated in the discovery cohort) and the corresponding genotype dosages (P S, reported only for replication cohorts). β S denotes the coefficient of regression of genotype dosage onto the phenotypic score. Consistency of effects was performed by testing the correlation of partial genotype-phenotype correlations (r ρ) in the discovery and replication cohorts. EA, effect allele. Extended details are given in Supplementary Table 6.