Background Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organs, and disproportionately affects women and individuals of non-European ancestry. Here, we report the results of genotyping individuals of European Ancestry (EA), African American (AA), and Hispanic (Amerindian) American ancestry (HA) on the Immunochip (196,524 polymorphisms: 718 small insertion deletions, 195,806 SNPs).

Methods Genotype calling was completed in multiancestral batches (AA: 2,970 cases, 2,452 controls; EA: 6,748 cases, 11,516 controls; HA: 1,872 cases and 2,016 controls). Admixture estimates were computed using the program ADMIXTURE. To test for an association between a SNP and case/control status within an ancestry, a logistic regression analysis was computed adjusting for admixture factors as covariates. Transancestral meta-analysis was computed using the inverse normal method, weighted by sample size. The EA SLE-risk allele genetic load was computed as the weighted (log of the odds ratio (OR)) and unweighted sum of the number of EA risk alleles. The genetic load was computed in an independent set of EA 2000 cases and 2000 controls, and AA and HA samples. Individuals whose genetic load (risk allele count) was in the lower 10% of the count distribution were the reference group.

Results In total, 9, 58, and 6 distinct non-HLA regions had P < 1x10E-6 (Bonferroni threshold) for the AA, EA, and HA cohorts, respectively. The three-ancestry meta-analysis was particularly informative for 22 additional SLE-associated regions that met P < 5x10E-8: 11 novel regions, 3 published regions now genome-significance, a complex multigenic region identified by adjusting for HLA alleles, and 7 established regions more sharply localised by transancestral mapping or novel to these ancestries

Genetic load was strongly predictive of SLE status in the 2000 EA cases/controls that were independent from the discovery set (OR_unweighted > 30 and OR_weighted >100). There was a greater than additive effect in the log(OR) (i.e., β parameter denoting slope) for the highest quarter of the genetic load range, suggesting the cumulative effect is greater than the sum of the individual effects (cumulative hit hypothesis). HA and AA showed markedly smaller ORs (between 3 and 10), reflecting a reduced predictive ability of EA-identified SLE risk loci in non-EA populations and the lack of capturing non-EA SLE risk loci on the Immunochip.

Conclusion The multiancestral analysis of the Immunochip data identified numerous novel SNP associations. The genetic load leads us to posit a cumulative hit hypothesis, where the cumulative effect is greater than the sum of the individual alleles’ effects.