Table 1. Effect sizes of common HLA haplotypes with significant non-additive effects.
Additive and non-additive effect sizes are shown for all haplotypes with significant non-additive disease contribution in rheumatoid arthritis (RA: HLA-DRB1), type 1 diabetes (T1D: HLA-DRB1-DQA1-DQB1), psoriasis vulgaris (PsV: HLA-C), and celiac disease (CeD: HLA-DQA1-DQB1). For diseases associated with multiple HLA loci, linked classical alleles across those loci were analyzed as haplotypes. P-values indicate the significance of improvement in fit of separate haplotype-specific models after sequentially including the additive and the non-additive term for a given haplotype. Odds ratios (OR) and 95% confidence intervals (CI) are given for a purely additive scenario (equivalent to a in Fig. 2a) and for a non-additive scenario, in which heterozygotes and homozygotes have separate effects (equivalent to a+d and 2a in Fig. 2a, respectively). Haplotypes are ordered by significance of the non-additive effect within each dataset.
| Disease | Loci | Additive model | Non-additive model (add. + non-add. component) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HLA-C | HLA-DRB1 | HLA-DQA1 | HLA-DQB1 | P | OR | 95% CI | P | Heterozygote effect | Homozygote effect | |||
| OR | 95% CI | OR | 95% CI | |||||||||
| RA | 01:01 | 1.6×10−22 | 1.54 | (1.41–1.68) | 1.3×10−8 | 1.77 | (1.61–1.96) | 1.17 | (0.87–1.58) | |||
| 04:01 | 2.0×10−206 | 3.31 | (3.05–3.59) | 1.4×10−7 | 3.93 | (3.54–4.36) | 8.34 | (6.87–10.12) | ||||
| 03:01 | 1.2×10−51 | 0.50 | (0.45–0.55) | 8.6×10−4 | 0.54 | (0.49–0.61) | 0.15 | (0.10–0.22) | ||||
| 15:01 | 7.7×10−43 | 0.55 | (0.51–0.60) | 1.2×10−3 | 0.60 | (0.54–0.67) | 0.21 | (0.15–0.28) | ||||
| T1D | 07:01 | 02:01 | 02:02 | 4.2 ×10−50 | 0.38 | (0.33–0.43) | 1.9×10−5 | 0.32 | (0.28–0.37) | 0.31 | (0.20–0.48) | |
| 04:01 | 03:01 | 03:01 | 2.2×10−167 | 0.18 | (0.16–0.21) | 3.4×10−5 | 0.20 | (0.18–0.23) | 0.005 | (0.001–0.018) | ||
| 04:01 | 03:01 | 03:02 | 5.4×10−224 | 6.09 | (5.38–6.90) | 3.5×10−5 | 6.72 | (5.88–7.68) | 13.86 | (8.79–21.86) | ||
| 03:01 | 05:01 | 02:01 | 5.2×10−35 | 1.70 | (1.56–1.85) | 3.5×10−3 | 1.92 | (1.71–2.16) | 2.55 | (2.12–3.08) | ||
| PsV | 06:02 | 1.5×10−92 | 2.94 | (2.65–3.28) | 4.9×10−8 | 3.49 | (3.09–3.95) | 4.28 | (3.11–5.87) | |||
| CeD | 02:01 | 02:02 | 1.3 ×10−67 | 1.86 | (1.73–1.99) | 6.7×10−62 | 2.36 | (2.18–2.55) | 0.36 | (0.27–0.50) | ||
| 05:01 | 03:01 | 5.3×10−156 | 0.35 | (0.32–0.38) | 3.0×10−25 | 0.42 | (0.39–0.46) | 0.03 | (0.02–0.04) | |||
| 05:01 | 02:01 | 4.3×10−675 | 5.78 | (5.38–6.20) | 4.7×10−19 | 7.28 | (6.67–7.95) | 22.80 | (19.43–26.75) | |||
| 03:01 | 03:02 | 8.5×10−67 | 0.50 | (0.46–0.54) | 3.5×10−11 | 0.43 | (0.39–0.47) | 0.55 | (0.42–0.73) | |||
| 01:01 | 05:01 | 4.0×10−216 | 0.27 | (0.25–0.29) | 3.2×10−6 | 0.29 | (0.26–0.32) | 0.02 | (0.01–0.04) | |||