Transancestral mapping and genetic load in systemic lupus erythematosus

Carl D. Langefeld, Hannah C. Ainsworth, Deborah S.Cunninghame Graham, Jennifer A. Kelly, Mary E. Comeau, Miranda C. Marion, Timothy D. Howard, Paula S. Ramos, Jennifer A. Croker, David L. Morris, Johanna K. Sandling, Jonas Carlsson Almlöf, Eduardo M. Acevedo-Vásquez, Graciela S. Alarcón, Alejandra M. Babini, Vicente Baca, Anders A. Bengtsson, Guillermo A. Berbotto, Marc Bijl, Elizabeth E. BrownHermine I. Brunner, Mario H. Cardiel, Luis Catoggio, Ricard Cervera, Jorge M. Cucho-Venegas, Solbritt Rantapää Dahlqvist, Sandra D'Alfonso, Berta Martins Da Silva, Inígo De La RúaFigueroa, Andrea Doria, Jeffrey C. Edberg, Emoke Endreffy, Jorge A. Esquivel-Valerio, Paul R. Fortin, Barry I. Freedman, Johan Frostegård, Mercedes A. Garcýá, Ignacio Garcýá De La Torre, Gary S. Gilkeson, Dafna D. Gladman, Iva Gunnarsson, Joel M. Guthridge, Jennifer L. Huggins, Judith A. James, Cees G.M. Kallenberg, Diane L. Kamen, David R. Karp, Kenneth M. Kaufman, Leah C. Kottyan, László Kovács, Helle Laustrup, Bernard R. Lauwerys, Quan Zhen Li, Marco A. Maradiaga-Ceceną, Javier Martín, Joseph M. McCune, David R. McWilliams, Joan T. Merrill, Pedro Miranda, José F. Moctezuma, Swapan K. Nath, Timothy B. Niewold, Lorena Orozco, Norberto Ortego-Centeno, Michelle Petri, Christian A. Pineau, Bernardo A. Pons-Estel, Janet Pope, Prithvi Raj, Rosalind Ramsey-Goldman, John D. Reveille, Laurie P. Russell, José M. Sabio, Carlos A. Aguilar-Salinas, Hugo R. Scherbarth, Raffaella Scorza, Michael F. Seldin, Christopher Sjöwall, Elisabet Svenungsson, Susan D. Thompson, Sergio M.A. Toloza, Lennart Truedsson, Teresa Tusié-Luna, Carlos Vasconcelos, Luis M. Vilá, Daniel J. Wallace, Michael H. Weisman, Joan E. Wither, Tushar Bhangale, Jorge R. Oksenberg, John D. Rioux, Peter K. Gregersen, Ann Christine Syvänen, Lars Rönnblom, Lindsey A. Criswell, Chaim O. Jacob, Kathy L. Sivils, Betty P. Tsao, Laura E. Schanberg, Timothy W. Behrens, Earl D. Silverman, Marta E. Alarcón-Riquelme, Robert P. Kimberly, John B. Harley, Edward K. Wakeland, Robert R. Graham, Patrick M. Gaffney, Timothy J. Vyse

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number16021
JournalNature communications
Volume8
DOIs
StatePublished - Jul 17 2017

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Langefeld, C. D., Ainsworth, H. C., Graham, D. S. C., Kelly, J. A., Comeau, M. E., Marion, M. C., Howard, T. D., Ramos, P. S., Croker, J. A., Morris, D. L., Sandling, J. K., Almlöf, J. C., Acevedo-Vásquez, E. M., Alarcón, G. S., Babini, A. M., Baca, V., Bengtsson, A. A., Berbotto, G. A., Bijl, M., ... Vyse, T. J. (2017). Transancestral mapping and genetic load in systemic lupus erythematosus. Nature communications, 8, [16021]. https://doi.org/10.1038/ncomms16021