Transancestral mapping and genetic load in systemic lupus erythematosus

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; Inígo De La RúaFigueroa; Andrea Doria; Jeffrey C. Edberg; Emoke Endreffy; Jorge A. Esquivel-Valerio; Paul R. Fortin; Barry I. Freedman; Johan Frostegård; Mercedes A. Garcýá; Ignacio Garcýá 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-Ceceną; 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

doi:10.1038/ncomms16021

Transancestral mapping and genetic load in systemic lupus erythematosus

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. BrownHermine I. Brunner, Mario H. Cardiel, Luis Catoggio, Ricard Cervera, Jorge M. Cucho-Venegas, Solbritt Rantapää Dahlqvist, Sandra D'Alfonso, Berta Martins Da Silva, Inígo De La RúaFigueroa, Andrea Doria, Jeffrey C. Edberg, Emoke Endreffy, Jorge A. Esquivel-Valerio, Paul R. Fortin, Barry I. Freedman, Johan Frostegård, Mercedes A. Garcýá, Ignacio Garcýá 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-Ceceną, 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

School of Medicine

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134 Scopus citations

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.

Original language	English (US)
Article number	16021
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms16021
State	Published - Jul 17 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Langefeld, C. D., Ainsworth, H. C., Graham, D. S. C., Kelly, J. A., Comeau, M. E., Marion, M. C., Howard, T. D., Ramos, P. S., Croker, J. A., Morris, D. L., Sandling, J. K., Almlöf, J. C., Acevedo-Vásquez, E. M., Alarcón, G. S., Babini, A. M., Baca, V., Bengtsson, A. A., Berbotto, G. A., Bijl, M., ... Vyse, T. J. (2017). Transancestral mapping and genetic load in systemic lupus erythematosus. Nature communications, 8, Article 16021. https://doi.org/10.1038/ncomms16021

Langefeld, CD, Ainsworth, HC, Graham, DSC, Kelly, JA, Comeau, ME, Marion, MC, Howard, TD, Ramos, PS, Croker, JA, Morris, DL, Sandling, JK, Almlöf, JC, Acevedo-Vásquez, EM, Alarcón, GS, Babini, AM, Baca, V, Bengtsson, AA, Berbotto, GA, Bijl, M, Brown, EE, Brunner, HI, Cardiel, MH, Catoggio, L, Cervera, R, Cucho-Venegas, JM, Dahlqvist, SR, D'Alfonso, S, Da Silva, BM, De La RúaFigueroa, I, Doria, A, Edberg, JC, Endreffy, E, Esquivel-Valerio, JA, Fortin, PR, Freedman, BI, Frostegård, J, Garcýá, MA, De La Torre, IG, Gilkeson, GS, Gladman, DD, Gunnarsson, I, Guthridge, JM, Huggins, JL, James, JA, Kallenberg, CGM, Kamen, DL, Karp, DR, Kaufman, KM, Kottyan, LC, Kovács, L, Laustrup, H, Lauwerys, BR, Li, QZ, Maradiaga-Ceceną, MA, Martín, J, McCune, JM, McWilliams, DR, Merrill, JT, Miranda, P, Moctezuma, JF, Nath, SK, Niewold, TB, Orozco, L, Ortego-Centeno, N, Petri, M, Pineau, CA, Pons-Estel, BA, Pope, J, Raj, P, Ramsey-Goldman, R, Reveille, JD, Russell, LP, Sabio, JM, Aguilar-Salinas, CA, Scherbarth, HR, Scorza, R, Seldin, MF, Sjöwall, C, Svenungsson, E, Thompson, SD, Toloza, SMA, Truedsson, L, Tusié-Luna, T, Vasconcelos, C, Vilá, LM, Wallace, DJ, Weisman, MH, Wither, JE, Bhangale, T, Oksenberg, JR, Rioux, JD, Gregersen, PK, Syvänen, AC, Rönnblom, L, Criswell, LA, Jacob, CO, Sivils, KL, Tsao, BP, Schanberg, LE, Behrens, TW, Silverman, ED, Alarcón-Riquelme, ME, Kimberly, RP, Harley, JB, Wakeland, EK, Graham, RR, Gaffney, PM & Vyse, TJ 2017, 'Transancestral mapping and genetic load in systemic lupus erythematosus', Nature communications, vol. 8, 16021. https://doi.org/10.1038/ncomms16021

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title = "Transancestral mapping and genetic load in systemic lupus erythematosus",

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.",

author = "Langefeld, {Carl D.} and Ainsworth, {Hannah C.} and Graham, {Deborah S.Cunninghame} and Kelly, {Jennifer A.} and Comeau, {Mary E.} and Marion, {Miranda C.} and Howard, {Timothy D.} and Ramos, {Paula S.} and Croker, {Jennifer A.} and Morris, {David L.} and Sandling, {Johanna K.} and Alml{\"o}f, {Jonas Carlsson} and Acevedo-V{\'a}squez, {Eduardo M.} and Alarc{\'o}n, {Graciela S.} and Babini, {Alejandra M.} and Vicente Baca and Bengtsson, {Anders A.} and Berbotto, {Guillermo A.} and Marc Bijl and Brown, {Elizabeth E.} and Brunner, {Hermine I.} and Cardiel, {Mario H.} and Luis Catoggio and Ricard Cervera and Cucho-Venegas, {Jorge M.} and Dahlqvist, {Solbritt Rantap{\"a}{\"a}} and Sandra D'Alfonso and {Da Silva}, {Berta Martins} and {De La R{\'u}aFigueroa}, In{\'i}go and Andrea Doria and Edberg, {Jeffrey C.} and Emoke Endreffy and Esquivel-Valerio, {Jorge A.} and Fortin, {Paul R.} and Freedman, {Barry I.} and Johan Frosteg{\aa}rd and Garc{\'y}{\'a}, {Mercedes A.} and {De La Torre}, {Ignacio Garc{\'y}{\'a}} and Gilkeson, {Gary S.} and Gladman, {Dafna D.} and Iva Gunnarsson and Guthridge, {Joel M.} and Huggins, {Jennifer L.} and James, {Judith A.} and Kallenberg, {Cees G.M.} and Kamen, {Diane L.} and Karp, {David R.} and Kaufman, {Kenneth M.} and Kottyan, {Leah C.} and L{\'a}szl{\'o} Kov{\'a}cs and Helle Laustrup and Lauwerys, {Bernard R.} and Li, {Quan Zhen} and Maradiaga-Cecen{\c a}, {Marco A.} and Javier Mart{\'i}n and McCune, {Joseph M.} and McWilliams, {David R.} and Merrill, {Joan T.} and Pedro Miranda and Moctezuma, {Jos{\'e} F.} and Nath, {Swapan K.} and Niewold, {Timothy B.} and Lorena Orozco and Norberto Ortego-Centeno and Michelle Petri and Pineau, {Christian A.} and Pons-Estel, {Bernardo A.} and Janet Pope and Prithvi Raj and Rosalind Ramsey-Goldman and Reveille, {John D.} and Russell, {Laurie P.} and Sabio, {Jos{\'e} M.} and Aguilar-Salinas, {Carlos A.} and Scherbarth, {Hugo R.} and Raffaella Scorza and Seldin, {Michael F.} and Christopher Sj{\"o}wall and Elisabet Svenungsson and Thompson, {Susan D.} and Toloza, {Sergio M.A.} and Lennart Truedsson and Teresa Tusi{\'e}-Luna and Carlos Vasconcelos and Vil{\'a}, {Luis M.} and Wallace, {Daniel J.} and Weisman, {Michael H.} and Wither, {Joan E.} and Tushar Bhangale and Oksenberg, {Jorge R.} and Rioux, {John D.} and Gregersen, {Peter K.} and Syv{\"a}nen, {Ann Christine} and Lars R{\"o}nnblom and Criswell, {Lindsey A.} and Jacob, {Chaim O.} and Sivils, {Kathy L.} and Tsao, {Betty P.} and Schanberg, {Laura E.} and Behrens, {Timothy W.} and Silverman, {Earl D.} and Alarc{\'o}n-Riquelme, {Marta E.} and Kimberly, {Robert P.} and Harley, {John B.} and Wakeland, {Edward K.} and Graham, {Robert R.} and Gaffney, {Patrick M.} and Vyse, {Timothy J.}",

year = "2017",

month = jul,

day = "17",

doi = "10.1038/ncomms16021",

language = "English (US)",

volume = "8",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Transancestral mapping and genetic load in systemic lupus erythematosus

AU - Langefeld, Carl D.

AU - Ainsworth, Hannah C.

AU - Graham, Deborah S.Cunninghame

AU - Kelly, Jennifer A.

AU - Comeau, Mary E.

AU - Marion, Miranda C.

AU - Howard, Timothy D.

AU - Ramos, Paula S.

AU - Croker, Jennifer A.

AU - Morris, David L.

AU - Sandling, Johanna K.

AU - Almlöf, Jonas Carlsson

AU - Acevedo-Vásquez, Eduardo M.

AU - Alarcón, Graciela S.

AU - Babini, Alejandra M.

AU - Baca, Vicente

AU - Bengtsson, Anders A.

AU - Berbotto, Guillermo A.

AU - Bijl, Marc

AU - Brown, Elizabeth E.

AU - Brunner, Hermine I.

AU - Cardiel, Mario H.

AU - Catoggio, Luis

AU - Cervera, Ricard

AU - Cucho-Venegas, Jorge M.

AU - Dahlqvist, Solbritt Rantapää

AU - D'Alfonso, Sandra

AU - Da Silva, Berta Martins

AU - De La RúaFigueroa, Inígo

AU - Doria, Andrea

AU - Edberg, Jeffrey C.

AU - Endreffy, Emoke

AU - Esquivel-Valerio, Jorge A.

AU - Fortin, Paul R.

AU - Freedman, Barry I.

AU - Frostegård, Johan

AU - Garcýá, Mercedes A.

AU - De La Torre, Ignacio Garcýá

AU - Gilkeson, Gary S.

AU - Gladman, Dafna D.

AU - Gunnarsson, Iva

AU - Guthridge, Joel M.

AU - Huggins, Jennifer L.

AU - James, Judith A.

AU - Kallenberg, Cees G.M.

AU - Kamen, Diane L.

AU - Karp, David R.

AU - Kaufman, Kenneth M.

AU - Kottyan, Leah C.

AU - Kovács, László

AU - Laustrup, Helle

AU - Lauwerys, Bernard R.

AU - Li, Quan Zhen

AU - Maradiaga-Ceceną, Marco A.

AU - Martín, Javier

AU - McCune, Joseph M.

AU - McWilliams, David R.

AU - Merrill, Joan T.

AU - Miranda, Pedro

AU - Moctezuma, José F.

AU - Nath, Swapan K.

AU - Niewold, Timothy B.

AU - Orozco, Lorena

AU - Ortego-Centeno, Norberto

AU - Petri, Michelle

AU - Pineau, Christian A.

AU - Pons-Estel, Bernardo A.

AU - Pope, Janet

AU - Raj, Prithvi

AU - Ramsey-Goldman, Rosalind

AU - Reveille, John D.

AU - Russell, Laurie P.

AU - Sabio, José M.

AU - Aguilar-Salinas, Carlos A.

AU - Scherbarth, Hugo R.

AU - Scorza, Raffaella

AU - Seldin, Michael F.

AU - Sjöwall, Christopher

AU - Svenungsson, Elisabet

AU - Thompson, Susan D.

AU - Toloza, Sergio M.A.

AU - Truedsson, Lennart

AU - Tusié-Luna, Teresa

AU - Vasconcelos, Carlos

AU - Vilá, Luis M.

AU - Wallace, Daniel J.

AU - Weisman, Michael H.

AU - Wither, Joan E.

AU - Bhangale, Tushar

AU - Oksenberg, Jorge R.

AU - Rioux, John D.

AU - Gregersen, Peter K.

AU - Syvänen, Ann Christine

AU - Rönnblom, Lars

AU - Criswell, Lindsey A.

AU - Jacob, Chaim O.

AU - Sivils, Kathy L.

AU - Tsao, Betty P.

AU - Schanberg, Laura E.

AU - Behrens, Timothy W.

AU - Silverman, Earl D.

AU - Alarcón-Riquelme, Marta E.

AU - Kimberly, Robert P.

AU - Harley, John B.

AU - Wakeland, Edward K.

AU - Graham, Robert R.

AU - Gaffney, Patrick M.

AU - Vyse, Timothy J.

PY - 2017/7/17

Y1 - 2017/7/17

N2 - 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.

AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85024906085&partnerID=8YFLogxK

U2 - 10.1038/ncomms16021

DO - 10.1038/ncomms16021

M3 - Article

C2 - 28714469

AN - SCOPUS:85024906085

SN - 2041-1723

VL - 8

JO - Nature communications

JF - Nature communications

M1 - 16021

ER -

Transancestral mapping and genetic load in systemic lupus erythematosus

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