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Nat Commun. 2017 Jul 17;8:16021. doi: 10.1038/ncomms16021.

Transancestral mapping and genetic load in systemic lupus erythematosus.

Langefeld CD1,2, Ainsworth HC1,2, Cunninghame Graham DS3, Kelly JA4, Comeau ME1,2, Marion MC1,2, Howard TD1,5, Ramos PS6,7, Croker JA8, Morris DL3, Sandling JK9, Almlöf JC9, Acevedo-Vásquez EM10, Alarcón GS8, Babini AM11, Baca V12, Bengtsson AA13, Berbotto GA14, Bijl M15, Brown EE8, Brunner HI16, Cardiel MH17, Catoggio L18, Cervera R19, Cucho-Venegas JM10, Dahlqvist SR20, D'Alfonso S21, Da Silva BM22, de la Rúa Figueroa I23, Doria A24, Edberg JC8, Endreffy E25, Esquivel-Valerio JA26, Fortin PR27, Freedman BI1,28, Frostegård J29, García MA30, de la Torre IG31, Gilkeson GS7, Gladman DD32, Gunnarsson I33, Guthridge JM4, Huggins JL16, James JA4,34, Kallenberg CGM35, Kamen DL7, Karp DR36, Kaufman KM37, Kottyan LC37, Kovács L38, Laustrup H39, Lauwerys BR40, Li QZ36, Maradiaga-Ceceña MA41, Martín J42, McCune JM43, McWilliams DR1,2, Merrill JT4, Miranda P44, Moctezuma JF45, Nath SK4, Niewold TB46, Orozco L47, Ortego-Centeno N48, Petri M49, Pineau CA50, Pons-Estel BA51, Pope J52, Raj P36, Ramsey-Goldman R53, Reveille JD54, Russell LP1,2, Sabio JM55, Aguilar-Salinas CA56, Scherbarth HR57, Scorza R58, Seldin MF59, Sjöwall C60, Svenungsson E33, Thompson SD37, Toloza SMA61, Truedsson L62, Tusié-Luna T63, Vasconcelos C64, Vilá LM65, Wallace DJ66, Weisman MH66, Wither JE32, Bhangale T67, Oksenberg JR68, Rioux JD69, Gregersen PK70, Syvänen AC9, Rönnblom L71, Criswell LA72, Jacob CO73, Sivils KL4, Tsao BP7, Schanberg LE74, Behrens TW67, Silverman ED75, Alarcón-Riquelme ME4,76,77, Kimberly RP8, Harley JB37, Wakeland EK36, Graham RR67, Gaffney PM4, Vyse TJ3.

Author information

1
Center for Public Health Genomics, Wake Forest School of Medicine, Winston-Salem, North Carolina 27101, USA.
2
Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina 27101, USA.
3
Divisions of Genetics and Molecular Medicine and Immunology, Infection and Inflammatory Diseases, King's College London, Guy's Hospital, London SE1 9RT, UK.
4
Arthritis &Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
5
Center for Human Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, North Carolina 27101, USA.
6
Department of Public Health Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
7
Department of Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
8
Division of Clinical Immunology and Rheumatology, UAB School of Medicine, Birmingham, Alabama 35294, USA.
9
Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala 752 36, Sweden.
10
Departamento de Reumatología, Hospital G. Almenara y Facultad de Medicina, Universidad Nacional Mayor de San Marcos, Lima 15081, Perú.
11
Hospital Italiano de Córdoba, Córdoba X5004BAL, Argentina.
12
Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico.
13
Department of Clinical Sciences, Rheumatology, Lund University, Lund 22362, Sweden.
14
Hospital Eva Perón, Granadero Baigorria S2152EDD, Argentina.
15
Department of Internal Medicine and Rheumatology, Martini Hospital, Van Swietenplein 1, 9728, NT, Groningen, The Netherlands.
16
Division of Rheumatology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, Ohio 45229, USA.
17
Centro de Investigación Clínica de Morelia, Morelia, Michoacán 58070, Mexico.
18
Hospital Italiano de Buenos Aires, 1181, Buenos Aires C1181ACH, Argentina.
19
Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Barcelona, Catalonia 08007, Spain.
20
Department of Public Health and Clinical Medicine, Division of Rheumatology, Umeå University, Umeå 901 87, Sweden.
21
Department of Health Sciences and Institute of Research in Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara 28100, Italy.
22
Unidade Multidisciplinar em Investigação Biomédica/Instituto de Ciências Biomédicas de Abel Salazar-Universidade do Porto, Porto 4099-003, Portugal.
23
Department of Rheumatology, Hospital Universitario de Gran Canaria Dr Negrín, Las Palmas de Gran Canaria 35010, Spain.
24
Division of Rheumatology, Department of Medicine (DIMED), University of Padua, Padua 35122, Italy.
25
Department of Pediatrics and Child Health Center, Albert Szent-Györgyi Medical Center, Faculty of Medicine, University of Szeged, Szeged H-6720, Hungary.
26
Hospital Universitario 'Dr José Eleuterio González' Universidad Autonoma de Nuevo León, Monterrey 64020, México.
27
CHU de Québec Université Laval, Québec, Canada G1R 2JG.
28
Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina 27101, USA.
29
Institute of Environmental Medicine, Unit of Immunology and Chronic diseases, Karolinska Institutet, Stockholm 171 77, Sweden.
30
Division of Rheumatology, Hospital Interzonal General de Agudos General San Martín, La Plata 1900, Argentina.
31
University of Guadalajara, Departamento de Fisiología, Guadalajara, Jalisco 44100, Mexico.
32
Centre for Prognosis Studies in The Rheumatic Diseases, Krembil Research Institute, Toronto Western Hospital, Toronto, Ontario M5T 2S8, Canada.
33
Unit of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm SE-171 76, Sweden.
34
Departments of Medicine and Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
35
Department of Rheumatology and Clinical Immunology,University Medical Center Groningen,University of Groningen, Groningen 9713 GZ, The Netherlands.
36
Department of Immunology, University of Texas SouthWestern Medical Center, Dallas, Texas 75235, USA.
37
Department of Pediatrics, Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
38
Department of Rheumatology, Albert Szent-Györgyi Medical Centre, University of Szeged, Szeged H-6720, Hungary.
39
Department of Rheumatology, Odense University Hospital, Odense 5000, Denmark.
40
Rheumatology, Cliniques Universitaires Saint-Luc &Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Louvain-la-Neuve 1348, Belgium.
41
Hospital General de Culiacán, Sinaloa 80220, Mexico.
42
Instituto de Parasitología y Biomedicina López Neyra, CSIC, Granada 18100, Spain.
43
University of Michigan Medical Center, Ann Arbor, Michigan 48103, USA.
44
Centro de Estudios Reumatológicos, Santiago de Chile, Santiago 7500000, Chile.
45
Departamento de Reumatología, Hospital General de México, Mexico D.F., Mexico.
46
Department of Rheumatology, Mayo Clinic, Rochester, Minnesota 94158, USA.
47
Instituto Nacional de Medicina Genómica (INMEGEN), México City 14610, México.
48
Unidad de Enfermedades Autoimmunes Sistémicas, UGC Medicina Interna, Hospital Universitario San Cecilio, Granada 18007, Spain.
49
Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21218, USA.
50
Rheumatology Division, McGill University, Montreal, Quebec H3A 0G4, Canada.
51
Department of Rheumatology, Sanatorio Parque, Rosario S2000, Argentina.
52
University of Western Ontario, London, Ontario, Canada M5T 2S8.
53
Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
54
The University of Texas Health Science Center at Houston (UTHealth) Medical School, Houston, Texas 77030, USA.
55
Hospital Universitario Virgen de las Nieves, Granada 18014, Spain.
56
Instituto Nacional de Ciencias Médicas y Nutrición, Department of Endocrinology and Metabolism, Vasco de Quiroga 15, Mexico City 14080, Mexico.
57
Unidad Reumatología y Enfermedades Autoinmunes H.I.G.A. Dr Alende Mar del Plata, Buenos Aires B7600, Argentina.
58
Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca'Granda Ospedale Ma Repiore Policlinico and University of Milan, Milan 20122, Italy.
59
Department of Biochemistry and Molecular Medicine, UC Davis School of Medicine, Sacramento, California 95616, USA.
60
Rheumatology Division of Neuro and Inflammation Sciences, Department of Clinical and Experimental Medicine, Linköping University, Linköping 581 83, Sweden.
61
Ministry of Health, San Fernando del Valle de Catamarca, Catamarca K4700, Argentina.
62
Department of Laboratory Medicine, Section of Microbiology, Immunology and Glycobiology, Lund University, Lund 221 00, Sweden.
63
Unidad de Biología Molecular y Medicina Genómica Instituto de Investigaciones Biomédicas/UNAM Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico.
64
Hospital Santo Antonio, Universidade do Porto, Porto 4099-003, Portugal.
65
University of Puerto Rico School of Medicine, San Juan 00936, Puerto Rico.
66
Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California 90048, USA.
67
Human Genetics, Genentech Inc, South San Francisco, California 94080, USA.
68
Department of Neurology and Institute of Human Genetics, University of California at San Francisco, San Francisco, California 94158, USA.
69
Université de Montréal and the Montreal Heart Institute, Montreal, Quebec, Canada H1T 1C8.
70
Center for Genomics &Human Genetics, The Feinstein Institute for Medical Research, Manhasset, New York 11030, USA.
71
Department of Medical Sciences, Rheumatology, Uppsala University, 752 36, Sweden.
72
Rosalind Russell/Ephraim P Engleman Rheumatology Research Center, Division of Rheumatology, UCSF School of Medicine, San Francisco, California 94158, USA.
73
Keck School of Medicine of USC, Los Angeles, California 90033, USA.
74
Department of Pediatrics, Duke University, Durham, North Carolina 27708, USA.
75
Department of Pediatrics and the Institute of Medical Sciences, The Hospital for Sick Children, Hospital for Sick Children Research Institute and University of Toronto, Ontario, Canada M5G 1X8.
76
Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), Granada 18007, Spain.
77
Unit of Institute of Environmental Medicine, Karolinska Institute, Solnavägen 171 77, Sweden.

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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