Transancestral mapping and genetic load in systemic lupus erythematosus.

Authors:
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 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

Nat Commun 2017 07 17;8:16021. Epub 2017 Jul 17.

Divisions of Genetics and Molecular Medicine and Immunology, Infection and Inflammatory Diseases, King's College London, Guy's Hospital, London SE1 9RT, UK.

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), 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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http://dx.doi.org/10.1038/ncomms16021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520018PMC
July 2017
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