Transancestral mapping and genetic load in systemic lupus erythematosus
Carl D. Langefeld(North Carolina Division of Public Health), Hannah C. Ainsworth(North Carolina Division of Public Health), Deborah S. Cunninghame Graham(Guy's Hospital), Jennifer A. Kelly(Oklahoma Medical Research Foundation), Mary E. Comeau(North Carolina Division of Public Health), Miranda C. Marion(North Carolina Division of Public Health), Timothy D. Howard(North Carolina Division of Public Health), Paula S. Ramos(Medical University of South Carolina), Jennifer A. Croker(University of Alabama at Birmingham Hospital), David Morris(Guy's Hospital), Johanna K. Sandling(Uppsala University), Jonas Carlsson Almlöf(Uppsala University), Eduardo M. Acevedo‐Vásquez(National University of San Marcos), Graciela S. Alarcón(University of Alabama at Birmingham Hospital), Alejandra Babini(Servicio Diabetología Hospital Córdoba), Vicente Baca(Mexican Social Security Institute), Anders Bengtsson(Lund University), Guillermo Berbotto(Baogang Group (China)), Marc Bijl(Martini Ziekenhuis), Elizabeth E. Brown(University of Alabama at Birmingham Hospital), Hermine I. Brunner(Cincinnati Children's Hospital Medical Center), Mario H. Cardiel(Universidad de Morelia), Luís J. Catoggio(Hospital Italiano de Buenos Aires), Ricard Cervera(Hospital Clínic de Barcelona), Jorge M. Cucho‐Venegas(National University of San Marcos), Solbritt Rantapää‐Dahlqvist(Umeå University), Sandra D’Alfonso(Università degli Studi del Piemonte Orientale “Amedeo Avogadro”), Berta Martins da Silva(Universidade do Porto), Iñigo de la Rúa Figueroa(Hospital Universitario de Gran Canaria Doctor Negrín), Andrea Doria(University of Padua), Jeffrey C. Edberg(University of Alabama at Birmingham Hospital), Emõke Endreffy(University of Szeged), Jorge Antonio Esquivel‐Valerio(Universidad Autónoma de Nuevo León), Paul R. Fortin(Université Laval), Barry I. Freedman(Wake Forest University), Johan Frostegård(Karolinska Institutet), Mercedes García(National University of General San Martín), Ignacio García‐De La Torre(Universidad de Guadalajara), Gary S. Gilkeson(Medical University of South Carolina), Dafna D. Gladman(Toronto Western Hospital), Iva Gunnarsson(Karolinska University Hospital), Joel M. Guthridge(Oklahoma Medical Research Foundation), Jennifer L. Huggins(Cincinnati Children's Hospital Medical Center), Judith A. James(Oklahoma Medical Research Foundation), Cees G. M. Kallenberg(University Medical Center Groningen), Diane L. Kamen(Medical University of South Carolina), David R. Karp(The University of Texas Southwestern Medical Center), Kenneth M. Kaufman(Cincinnati Children's Hospital Medical Center), Leah C. Kottyan(Cincinnati Children's Hospital Medical Center), László Kovács(University of Szeged), Helle Laustrup(Odense University Hospital), Bernard Lauwerys(Cliniques Universitaires Saint-Luc), Quan‐Zhen Li(The University of Texas Southwestern Medical Center), Marco A. Maradiaga‐Ceceña(Pediatric Hospital of Sinaloa), Javier Martı́n(Instituto de Parasitología y Biomedicina "López - Neyra"), Joseph M. McCune(University of Michigan), David R. McWilliams(North Carolina Division of Public Health), Joan T. Merrill(Oklahoma Medical Research Foundation), Pedro C. Miranda(Centro de Estudios Científicos), J. F. Moctezuma(Hospital General de México), Swapan K. Nath(Oklahoma Medical Research Foundation), Timothy B. Niewold(Mayo Clinic), Lorena Orozco(National Institute of Genomic Medicine), Norberto Ortego‐Centeno(Instituto de Investigación Biosanitaria de Granada), Michelle Petri(Johns Hopkins University), Christian A. Pineau(McGill University), Bernardo A. Pons‐Estel(Centro Científico Tecnólogico - Rosario), Janet Pope(Western University), Prithvi Raj(The University of Texas Southwestern Medical Center), Rosalind Ramsey‐Goldman(Northwestern University), John D. Reveille(The University of Texas Health Science Center), Laurie Russell(North Carolina Division of Public Health), José Mario Sabio(Hospital Universitario Virgen de las Nieves), Carlos A. Aguilar‐Salinas(Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán), Hugo R. Scherbarth(Centro Científico Tecnológico Mar del Plata), R Scorza(University of Milan), Michael F. Seldin(University of California, Davis), Christopher Sjöwall(Linköping University), Elisabet Svenungsson(Karolinska University Hospital), Susan D. Thompson(Cincinnati Children's Hospital Medical Center), Sergio Toloza(National University of Catamarca), Lennart Truedsson(Lund University), Teresa Tusié‐Luna(Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán), Carlos Vasconcelos(Universidade do Porto), Luis M. Vilá(University of Puerto Rico System), Daniel J. Wallace(Cedars-Sinai Medical Center), Michael H. Weisman(Cedars-Sinai Medical Center), Joan Wither(Toronto Western Hospital), Tushar Bhangale, Jorge R. Oksenberg(University of California, San Francisco), John D. Rioux(Montreal Heart Institute), Peter K. Gregersen(Feinstein Institute for Medical Research), Ann‐Christine Syvänen(Uppsala University), Lars Rönnblom(Uppsala University), Lindsey A. Criswell(Center for Rheumatology), Chaim O. Jacob(Keck Hospital of USC), Kathy L. Sivils(Oklahoma Medical Research Foundation), Betty P. Tsao(Medical University of South Carolina), Laura E. Schanberg(Duke University), Timothy W. Behrens, Earl D. Silverman(University of Toronto), Marta E. Alarcón‐Riquelme(Karolinska Institutet), Robert P. Kimberly(University of Alabama at Birmingham Hospital), John B. Harley(Cincinnati Children's Hospital Medical Center), Edward K. Wakeland(The University of Texas Southwestern Medical Center), Robert Graham, Patrick M. Gaffney(Oklahoma Medical Research Foundation), Timothy J. Vyse(Guy's Hospital)
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Abstract
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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