Transancestral mapping and genetic load in systemic lupus erythematosus

• Published in: Nature communications Vol. 8; no. 1; pp. 16021 - 18
• Main Authors: Langefeld, Carl D., Ainsworth, Hannah C., Graham, Deborah S. Cunninghame, Kelly, Jennifer A., Comeau, Mary E., Marion, Miranda C., Howard, Timothy D., Ramos, Paula S., Croker, Jennifer A., Morris, David L., Sandling, Johanna K., Almlöf, Jonas Carlsson, Acevedo-Vásquez, Eduardo M., Alarcón, Graciela S., Babini, Alejandra M., Baca, Vicente, Bengtsson, Anders A., Berbotto, Guillermo A., Bijl, Marc, Brown, Elizabeth E., Cardiel, Mario H., Catoggio, Luis, Cervera, Ricard, Cucho-Venegas, Jorge M., Dahlqvist, Solbritt Rantapää, D’Alfonso, Sandra, Da Silva, Berta Martins, de la Rúa Figueroa, Iñigo, Doria, Andrea, Edberg, Jeffrey C., Endreffy, Emőke, Esquivel-Valerio, Jorge A., Fortin, Paul R., Freedman, Barry I., Frostegård, Johan, García, Mercedes A., de la Torre, Ignacio García, Gilkeson, Gary S., Gunnarsson, Iva, Guthridge, Joel M., Huggins, Jennifer L., James, Judith A., Kallenberg, Cees G. M., Kamen, Diane L., Karp, David R., Kaufman, Kenneth M., Kovács, László, Lauwerys, Bernard R., Li, Quan-Zhen, Maradiaga-Ceceña, Marco A., Martín, Javier, McCune, Joseph M., McWilliams, David R., Merrill, Joan T., Miranda, Pedro, Moctezuma, José F., Nath, Swapan K., Niewold, Timothy B., Ortego-Centeno, Norberto, Petri, Michelle, Pineau, Christian A., Pons-Estel, Bernardo A., Pope, Janet, Raj, Prithvi, Reveille, John D., Russell, Laurie P., Sabio, José M., Aguilar-Salinas, Carlos A., Scorza, Raffaella, Seldin, Michael F., Sjöwall, Christopher, Svenungsson, Elisabet, Thompson, Susan D., Toloza, Sergio M. A., Truedsson, Lennart, Tusié-Luna, Teresa, Vasconcelos, Carlos, Vilá, Luis M., Wallace, Daniel J., Weisman, Michael H., Wither, Joan E., Bhangale, Tushar, Oksenberg, Jorge R., Rioux, John D., Gregersen, Peter K., Syvänen, Ann-Christine, Rönnblom, Lars, Criswell, Lindsey A., Sivils, Kathy L., Tsao, Betty P., Schanberg, Laura E., Behrens, Timothy W., Silverman, Earl D., Alarcón-Riquelme, Marta E., Kimberly, Robert P., Harley, John B., Wakeland, Edward K., Graham, Robert R., Gaffney, Patrick M., Vyse, Timothy J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.07.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 45/43; 692/308/2056; 692/699/249; 692/699/249/1313/1613; Age of Onset; American Indian or Alaska Native - genetics; Autoimmune diseases; Basic Medicine; Black People - genetics; Case studies; Case-Control Studies; Estudi de casos; Genetic Load; Genètica humana; Hispanic or Latino - genetics; HLA Antigens - genetics; Human genetics; Humanities and Social Sciences; Humans; Logistic Models; Lupus eritematós; Lupus erythematosus; Lupus Erythematosus, Systemic - genetics; Malalties autoimmunitàries; Medical and Health Sciences; Medical Genetics; Medical Genetics and Genomics (including Gene Therapy); Medicin och hälsovetenskap; Medicinsk genetik; Medicinsk genetik och genomik (Här ingår: Genterapi); Medicinska och farmaceutiska grundvetenskaper; multidisciplinary; Multifactorial Inheritance; Mutagenesis, Insertional; Polymorphism, Single Nucleotide; Science; Science (multidisciplinary); Sequence Deletion; White People - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms16021

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. Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong ethnic and gender bias. In a transancestral genetic association study, Langefeld et al . identify 24 novel regions associated with risk to lupus and propose a cumulative hits hypothesis for loci conferring risk to SLE.