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Transancestral mapping and genetic load in systemic lupus erythematosus

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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. Brown & 88 more Hermine I. Brunner, Mario H. Cardiel, Luis Catoggio, Ricard Cervera, Jorge M. Cucho-venegas, Solbritt Rantapää Dahlqvist, Sandra D’alfonso, Berta Martins Da Silva, Iñigo De La Rúa Figueroa, Andrea Doria, Jeffrey C. Edberg, Emőke Endreffy, Jorge A. Esquivel-valerio, Paul R. Fortin, Barry I. Freedman, Johan Frostegård, Mercedes A. García, Ignacio García 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-ceceña, 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

Original languageEnglish
Article number16021
Number of pages18
JournalNature Communications
Volume8
Issue number1
Early online date17 Jul 2017
DOIs
Accepted/In press23 May 2017
E-pub ahead of print17 Jul 2017
Published17 Jul 2017

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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.

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