Extended Data Fig. 4: Using C4 gene variation to understand the appearance of trans-ancestral disparity in MHC association signals, and to fine-map an additional genetic effect.

Association signals (for SLE and Sjögren’s syndrome) for variants in a multi-megabase region of human chromosome 6 containing the MHC region including the HLA and C4 genes. a, Relationship between SLE association (−log₁₀(p), y-axis) and LD to the weighted C4 risk score (x axis) for genetic markers and imputed HLA alleles across the extended MHC locus. In this European-ancestry cohort, it is unclear (from this analysis alone) whether the association with the markers in the predominant ray of points (at an angle of ~45° from the x axis) is driven by variation at C4 or by the long haplotype containing DRB1*03:01 (green), DQA1*05:01 (blue), B*08:01 (red) and many other SNPs (black). In addition, at least one independent association signal (a ray of points at a higher angle in the plot, with strong association signals and only weak linkage disequilibirum-based correlation to C4 and DRB1*0301) with some LD to DRB1*15:01 (maroon) is also present. b, Analysis as in a, but for associations to Sjögren’s syndrome in a cohort of European ancestry. As in SLE, it is initially unclear whether the genetic association signal is driven by variation at C4 or by linked HLA alleles, DRB1*03:01 (green), DQA1*05:01 (blue), and B*08:01 (red). There is also an independent association signal with LD to DRB1*15:01 (maroon). c, Analysis as in a, but of an African American SLE case–control cohort (in which LD in the MHC region is more limited). Many MHC-region SNPs associate with SLE in proportion to their LD with the weighted C4 risk score inferred from the earlier analysis of the European-ancestry cohort; this C4-derived risk score itself associates with SLE at P = 4.3 × 10⁻¹⁹ in a logistic regression on 1,494 SLE cases and 5,908 controls. No similarly strong association is observed for DRB1*03:01, DQA1*05:01 or B*08:01, HLA alleles which are in strong LD with C4 risk on European-ancestry (but not African American) haplotypes. An independent association signal is also present in this cohort, more clearly in LD with the DRB1*15:03 allele (maroon). d, LD in the European-ancestry SLE cohort between the composite C4 risk term (weighted sum of risk associated with various combinations of C4A and C4B from Fig. 2a) and variants in the MHC region as r² (y-axis). e, As in d, but for the African American SLE cohort. f, LD (to C4 composite risk) for the same variants in European-ancestry individuals (x axis) and African Americans (y axis). Note the abundance of variants that have greater LD with C4 risk among European-ancestry individuals than among African Americans. Also, several groups of variants have equivalent LD (to C4 risk) in European ancestry individuals but exhibit a range of LD to C4 risk among African Americans. g, Associations with SLE (−log₁₀ P values) for the same variants in European ancestry (x axis) and African American (y axis) case–control cohorts. Orange shading represents the extent of LD with C4 risk in European ancestry individuals. Variants with strong European-specific association to SLE are generally in strong LD with C4 risk among European-ancestry individuals. h, Comparison of the inferred effect size from association of genetic markers with SLE (unconditioned log odds ratios) among European-ancestry (x axis) and African American (y axis) research participants. As also seen in g, variants with discordant associations to SLE (across populations) tend also to be in strong LD to C4 risk among European-ancestry individuals. i, As in g, but now controlling for the effect of C4 variation in analysis of the European-ancestry cohort (x axis). Note that controlling for C4 risk in European-ancestry individuals alone greatly aligns (relative to g) the patterns of association between European ancestry and African American cohorts. j, As in i, but now also controlling for the effect of C4 in associations of the African American cohort. Note that due to the lack of strong LD relationships between C4 and variants in the MHC region in African Americans (e), this further adjustment does not change results strongly (relative to i). The independent signal, rs2105898, and HLA alleles, DRB1*15:01 and DRB1*15:03, are also highlighted. LD with rs2105898 in European-ancestry individuals is indicated by purple shading. k, Comparison of the inferred effect sizes from association of genetic markers with SLE (log odds ratios) controlling for C4-derived risk among European-ancestry (x axis) and African American (y axis) research participants. Two SNPs (rs2105898 and rs9271513) that form a short haplotype common to both ancestry groups are among the strongest associations in both cohorts. (Their association to SLE in the European-ancestry cohort was initially much less remarkable than that of other SNPs that are in strong LD with C4.) LD with rs2105898 in European-ancestry individuals is indicated by purple shading. l, As in i, but with variants shaded by whether they exhibit greater LD to rs2105898 in Europeans (blue) or African Americans (red).