Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P<5 × 10−8), refined association signals in established regions, extended associations to additional ancestries, and a disentangled complex HLA multigenic effect. The risk allele count (genetic load) exhibits an accelerating pattern of SLE risk, leading us to posit a cumulative hit hypothesis for autoimmune disease. Comparing results across the three ancestries identifies both ancestry-dependent and ancestry-independent contributions to SLE risk. Our results are consistent with the unique and complex histories of the populations sampled, and collectively help clarify the genetic architecture and ethnic disparities in SLE.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities
We report the results of genotyping large samples of individuals of European ancestry (EA), African American (AA) and Hispanic (Amerindian) American ancestry (HA) on the Illumina Infinium Immunochip (196,524 polymorphisms: 718 small insertion deletions, 195,806 single nucleotide polymorphisms (SNPs)), a microarray designed to perform both deep replication and fine mapping of established major autoimmune and inflammatory disease loci[9]
Differences in linkage disequilibrium (LD) contribute to this result, the highly reduced number of detected associations relative to expected, plus the genetic load analyses, strongly suggest that ancestryspecific and -independent loci contribute to SLE risk
Summary
SNP analyses within the HLA region provided strong evidence of association with SLE across groups (Fig. 2). These associations are complicated by the region’s extended LD between SNPs and classical HLA alleles. HLA allele associations for each ancestry and for multi-ancestral meta-analysis are shown in Supplementary Data 4. Two SNPs showed evidence of association with SLE (Supplementary Data 6) after adjusting for the HLA alleles identified in the stepwise modelling (Fig. 2). Transancestral meta-analysis showed stronger association at both loci (Supplementary Data 6 and Supplementary Fig. 6) Whether these residual associations reflect novel loci or imperfect imputation requires additional study. Rs12722558 10p15 6070276 IL2RA rs10905718 10p15 6114856 IL2RA rs112123005 10p15 6472492 IL2RA rs113304138d 10p15 6564277 IL2RA rs223881
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