VWF missense variants associated with VWF antigen and/or FVIII coagulant activity in AAs
| Variant (chromosome/BP) . | Rs number . | Annotation . | EAF AA . | EAF EA* . | Imputation quality (Rsq)† . | Functional prediction‡ . | N . | VWF β (SE) . | Ln(VWF) β (SE) . | Ln(VWF) P value . | N . | FVIII β (SE) . | Ln(FVIII) β (SE) . | Ln(FVIII) P value . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| chr12:6153534 | 1063856 | Thr789Ala | 0.58 | 0.3600 | 1.00 | Benign | 2976 | 8.62 (1.56) | 0.0664 (0.0109) | 1.05E-09 | 4432 | 7.22 (1.36) | 0.0377 (0.0078) | 1.24E-06 |
| chr12:6145649 | 57950734 | His817Gln | 0.11 | 0.0003 | 0.97 | Deleterious | 2976 | −4.74 (2.57) | −0.0317 (0.018) | .078 | 4432 | −17.8 (2.23) | 0.1205 (0.0127) | 1.77E-21 |
| chr12:6128446 | 11063988 | Ile1380Val | 0.11 | 0.00035 | 0.82 | Benign | 2934 | 6.33 (2.71) | 0.059 (0.0188) | .0017 | 4360 | 9.39 (2.42) | −0.0641 (0.0137) | 2.74E-06 |
| chr12:6128280 | 11063987 | Asn1435Ser | 0.11 | 0.00023 | 0.85 | Benign | 2976 | 6.05 (2.50) | 0.0555 (0.0186) | .0028 | 4432 | 9.72 (2.41) | 0.0647 (0.0135) | 1.71E-06 |
| chr12:6128269 | 150077670 | Met1439Val | 0.0044 | <1/12000 | 0.90 | Benign | 2543 | −34.5 (12.7) | −0.3279 (0.0958) | .00062 | 3838 | −15.6 (11.0) | −0.1186 (0.0665) | .074 |
| chr12:6128170 | 1800383 | Asp1472His | 0.393 | 0.066 | 0.85 | Benign | 2976 | 5.48 (1.66) | 0.038 (0.0125) | .0010 | 4432 | 2.52 (1.50) | 0.0183 (0.0095) | .055 |
| chr12:6128127 | 149424724 | Ser1486Leu | 0.008 | 0.0001 | 0.75 | Benign | 2967 | −40.3 (10.0) | −0.3585 (0.0677) | 1.18E-07 | 4420 | −9.68 (8.84) | −0.1200 (0.0494) | .015 |
| chr12:6103072 | 76342212 | Arg2185Gln | 0.19 | 0.0015 | 0.97 | Benign | 2973 | −13.1 (2.03) | −0.1013 (0.0141) | 6.24E-13 | 4428 | −13.1 (1.78) | −0.0856 (0.0101) | 1.86E-17 |
| chr12:6094771 | 61750625 | Arg2287Trp | 0.00763 | 0 | 0.70 | Deleterious | 2976 | −39.6 (9.71) | −0.3064 (0.0634) | 1.33E-06 | 4432 | −15.2 (8.78) | −0.1108 (0.0481) | .021 |
| Variant (chromosome/BP) . | Rs number . | Annotation . | EAF AA . | EAF EA* . | Imputation quality (Rsq)† . | Functional prediction‡ . | N . | VWF β (SE) . | Ln(VWF) β (SE) . | Ln(VWF) P value . | N . | FVIII β (SE) . | Ln(FVIII) β (SE) . | Ln(FVIII) P value . |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| chr12:6153534 | 1063856 | Thr789Ala | 0.58 | 0.3600 | 1.00 | Benign | 2976 | 8.62 (1.56) | 0.0664 (0.0109) | 1.05E-09 | 4432 | 7.22 (1.36) | 0.0377 (0.0078) | 1.24E-06 |
| chr12:6145649 | 57950734 | His817Gln | 0.11 | 0.0003 | 0.97 | Deleterious | 2976 | −4.74 (2.57) | −0.0317 (0.018) | .078 | 4432 | −17.8 (2.23) | 0.1205 (0.0127) | 1.77E-21 |
| chr12:6128446 | 11063988 | Ile1380Val | 0.11 | 0.00035 | 0.82 | Benign | 2934 | 6.33 (2.71) | 0.059 (0.0188) | .0017 | 4360 | 9.39 (2.42) | −0.0641 (0.0137) | 2.74E-06 |
| chr12:6128280 | 11063987 | Asn1435Ser | 0.11 | 0.00023 | 0.85 | Benign | 2976 | 6.05 (2.50) | 0.0555 (0.0186) | .0028 | 4432 | 9.72 (2.41) | 0.0647 (0.0135) | 1.71E-06 |
| chr12:6128269 | 150077670 | Met1439Val | 0.0044 | <1/12000 | 0.90 | Benign | 2543 | −34.5 (12.7) | −0.3279 (0.0958) | .00062 | 3838 | −15.6 (11.0) | −0.1186 (0.0665) | .074 |
| chr12:6128170 | 1800383 | Asp1472His | 0.393 | 0.066 | 0.85 | Benign | 2976 | 5.48 (1.66) | 0.038 (0.0125) | .0010 | 4432 | 2.52 (1.50) | 0.0183 (0.0095) | .055 |
| chr12:6128127 | 149424724 | Ser1486Leu | 0.008 | 0.0001 | 0.75 | Benign | 2967 | −40.3 (10.0) | −0.3585 (0.0677) | 1.18E-07 | 4420 | −9.68 (8.84) | −0.1200 (0.0494) | .015 |
| chr12:6103072 | 76342212 | Arg2185Gln | 0.19 | 0.0015 | 0.97 | Benign | 2973 | −13.1 (2.03) | −0.1013 (0.0141) | 6.24E-13 | 4428 | −13.1 (1.78) | −0.0856 (0.0101) | 1.86E-17 |
| chr12:6094771 | 61750625 | Arg2287Trp | 0.00763 | 0 | 0.70 | Deleterious | 2976 | −39.6 (9.71) | −0.3064 (0.0634) | 1.33E-06 | 4432 | −15.2 (8.78) | −0.1108 (0.0481) | .021 |
Linear regression models were initially run with natural-log–transformed VWF and FVIII level as the dependent variable, with adjustment for age, sex, and genetic ancestry (as inferred from principal component analysis), as described under “Methods.” The β coefficient corresponds to the mean difference in natural-log–transformed VWF or FVIII between an individual carrying 1 copy of the “effect allele” compared with individuals carrying 0 copies of the effect allele. The effect allele refers to the second amino acid under “Annotation.” Effect allele frequency indicates the frequency of the effect allele in AAs and EAs. To provide more clinically relevant mean VWF or FVIII effect sizes, β coefficients and standard errors per each additional copy of the minor allele were also reported for corresponding regression models using untransformed VWF or FVIII.
BP, base pair; EAF, effect allele frequency; SE, standard error.
Allele frequency data in EAs from NHLBI Exome Sequencing Project (ESP) Exome Variant Server (evs.gs.washington.edu/EVS/).
Imputation quality Rsq is an estimate of the correlation between the imputed genotype and the actual genotype and serves as a measure of imputation accuracy.
Functional prediction of the potential impact of the VWF missense variant was determined using the algorithm Condel (CONsensus DELeteriousness score of nonsynonymous single nucleotide variants), as described in supplemental Methods and in supplemental Table 2.