Transancestral mapping and genetic load in systemic lupus erythematosus

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 (similar to 50% of these regions have multiple independent associations); these include 24 novel SLE regions (P < 5 x 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.
We gratefully acknowledge the Alliance for Lupus Research for funding and support. The research was supported in part by awards from the Arthritis Research UK Special Strategic Award (ref. 19289) and from George Koukis (T.J.V.). In addition, the research was funded/supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London (T.J.V.). The work would not be possible without funding from the NIH grants AR049084 (RPK, EEB); the International Consortium on the Genetics of Systemic Lupus Erythematosus (SLEGEN) AI083194 (J.B.H.); CA141700, AR058621 Proyecto de Excelencia, Consejeria de Andalucia (M.E.A.R.); AR043814 and AR-065626 (B.P.T.); AR060366, MD007909, AI107176 (S.K.N.); AR-057172 (C.O.J.); RC2 AR058959, U19 A1082714, R01 AR063124, P30 GM110766, R01 AR056360 (P.M.G.); P60 AR053308 (L.A.C.), MUSC part is from UL1RR029882 (G.S.G., D.L.K.) and 5P60AR062755 (G.S.G., D.L.K., P.R.R.). Oklahoma Samples U19AI082714, U01AI101934, P30GM103510, U54GM104938 and P30AR053483 (J.A.J., J.M.G.); Northwestern P60 AR066464 and 1U54TR001018 (R.R.G.); This study was supported by the US National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH) under Award Numbers K01 AR067280 and P60 AR062755 (PSR); N01AR22265 (funded collection of APPLE samples) (LES) and the APPLE Investigators; R01AR43727, NIH AR 043727 and 069572 (M.P.); NIAMS/NIH P50-AR055503 (D.R.K.). We would like to also thank the RILITE foundation for financial support (C.D.L.). Additional funding for Immunochip genotyping was provided by Genentech.