Complement genes contribute sex-biased vulnerability in diverse disorders

Nolan Kamitaki; Aswin Sekar; Robert E. Handsaker; Heather de Rivera; Katherine Tooley; David L. Morris; Kimberly E. Taylor; Christopher W. Whelan; Philip Tombleson; Loes M. Olde Loohuis; Psychosis Endophenotypes International Consortium; Wellcome Trust Case–Control Consortium 2; Psychosis Endophenotype International Consortium; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Michael Boehnke; Robert P. Kimberly; Kenneth M. Kaufman; John B. Harley; Carl D. Langefeld; Christine E. Seidman; Michele T. Pato; Carlos N. Pato; Roel A. Ophoff; Robert R. Graham; Lindsey A. Criswell; Timothy J. Vyse; Steven A. McCarroll

doi:10.1038/s41586-020-2277-x

Complement genes contribute sex-biased vulnerability in diverse disorders

Nolan Kamitaki^*, Aswin Sekar, Robert E. Handsaker, Heather de Rivera, Katherine Tooley, David L. Morris, Kimberly E. Taylor, Christopher W. Whelan, Philip Tombleson, Loes M. Olde Loohuis, Psychosis Endophenotypes International Consortium, Wellcome Trust Case–Control Consortium 2, Psychosis Endophenotype International Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Michael Boehnke, Robert P. Kimberly, Kenneth M. Kaufman, John B. Harley, Carl D. Langefeld, Christine E. SeidmanMichele T. Pato, Carlos N. Pato, Roel A. Ophoff, Robert R. Graham, Lindsey A. Criswell, Timothy J. Vyse, Steven A. McCarroll

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3–6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren’s syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

Original language	English
Journal	Nature
Early online date	2020
DOIs	https://doi.org/10.1038/s41586-020-2277-x
Publication status	Published - 25 Jun 2020

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10.1038/s41586-020-2277-x

Cite this

Kamitaki, N., Sekar, A., Handsaker, R. E., de Rivera, H., Tooley, K., Morris, D. L., Taylor, K. E., Whelan, C. W., Tombleson, P., Loohuis, L. M. O., Psychosis Endophenotypes International Consortium, Wellcome Trust Case–Control Consortium 2, Psychosis Endophenotype International Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Boehnke, M., Kimberly, R. P., Kaufman, K. M., Harley, J. B., Langefeld, C. D., ... McCarroll, S. A. (2020). Complement genes contribute sex-biased vulnerability in diverse disorders. Nature. https://doi.org/10.1038/s41586-020-2277-x

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title = "Complement genes contribute sex-biased vulnerability in diverse disorders",

abstract = "Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sj{\"o}gren{\textquoteright}s syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sj{\"o}gren{\textquoteright}s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3–6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sj{\"o}gren{\textquoteright}s syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sj{\"o}gren{\textquoteright}s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sj{\"o}gren{\textquoteright}s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women{\textquoteright}s greater risk of SLE and Sj{\"o}gren{\textquoteright}s syndrome and men{\textquoteright}s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.",

author = "Nolan Kamitaki and Aswin Sekar and Handsaker, {Robert E.} and {de Rivera}, Heather and Katherine Tooley and Morris, {David L.} and Taylor, {Kimberly E.} and Whelan, {Christopher W.} and Philip Tombleson and Loohuis, {Loes M. Olde} and Stephan Ripke and Neale, {Benjamin M.} and Aiden Corvin and Walters, {James T. R.} and Kai-How Farh and Holmans, {Peter A.} and Phil Lee and Brendan Bulik-Sullivan and Collier, {David A.} and Hailiang Huang and Pers, {Tune H.} and Ingrid Agartz and Esben Agerbo and Margot Albus and Madeline Alexander and Farooq Amin and Bacanu, {Silviu A.} and Martin Begemann and Belliveau, {Richard A.} and Judit Bene and Bergen, {Sarah E.} and Elizabeth Bevilacqua and Bigdeli, {Tim B.} and Black, {Donald W.} and Richard Bruggeman and Buccola, {Nancy G.} and Buckner, {Randy L.} and William Byerley and Wiepke Cahn and Guiqing Cai and Cairns, {Murray J.} and Dominique Campion and Cantor, {Rita M.} and Carr, {Vaughan J.} and Noa Carrera and Catts, {Stanley V.} and Chambert, {Kimberly D.} and Chan, {Raymond C. K.} and Chen, {Ronald Y. L.} and Chen, {Eric Y. H.} and Wei Cheng and Cheung, {Eric F. C.} and Chong, {Siow Ann} and Cloninger, {C. Robert} and David Cohen and Nadine Cohen and Paul Cormican and Nick Craddock and Benedicto Crespo-Facorro and Crowley, {James J.} and David Curtis and Michael Davidson and Davis, {Kenneth L.} and Franziska Degenhardt and {del Favero}, Jurgen and DeLisi, {Lynn E.} and Ditte Demontis and Dimitris Dikeos and Timothy Dinan and Srdjan Djurovic and Gary Donohoe and Elodie Drapeau and Jubao Duan and Frank Dudbridge and Naser Durmishi and Peter Eichhammer and Johan Eriksson and Valentina Escott-Price and Laurent Essioux and Fanous, {Ayman H.} and Farrell, {Martilias S.} and Josef Frank and Lude Franke and Robert Freedman and Freimer, {Nelson B.} and Marion Friedl and Friedman, {Joseph I.} and Menachem Fromer and Giulio Genovese and Lyudmila Georgieva and Gershon, {Elliot S.} and Ina Giegling and Paola Giusti-Rodr{\'i}guez and Stephanie Godard and Goldstein, {Jacqueline I.} and Vera Golimbet and Srihari Gopal and Jacob Gratten and {de Haan}, Lieuwe and Marina Mitjans and Hamshere, {Marian L.} and Mark Hansen and Thomas Hansen and Vahram Haroutunian and Hartmann, {Annette M.} and Henskens, {Frans A.} and Stefan Herms and Hirschhorn, {Joel N.} and Per Hoffmann and Andrea Hofman and Hollegaard, {Mads V.} and Hougaard, {David M.} and Masashi Ikeda and Inge Joa and Antonio Juli{\`a} and Kahn, {Ren{\'e} S.} and Luba Kalaydjieva and Sena Karachanak-Yankova and Juha Karjalainen and David Kavanagh and Keller, {Matthew C.} and Kelly, {Brian J.} and Kennedy, {James L.} and Andrey Khrunin and Yunjung Kim and Janis Klovins and Knowles, {James A.} and Bettina Konte and Vaidutis Kucinskas and Kucinskiene, {Zita Ausrele} and Hana Kuzelova-Ptackova and K{\"a}hler, {Anna K.} and Claudine Laurent and Keong, {Jimmy Lee Chee} and Lee, {S. Hong} and Legge, {Sophie E.} and Bernard Lerer and Miaoxin Li and Tao Li and Kung-Yee Liang and Jeffrey Lieberman and Svetlana Limborska and Loughland, {Carmel M.} and {Jan Lubinski} and Jouko L{\"o}nnqvist and Milan Macek and Magnusson, {Patrik K. E.} and Maher, {Brion S.} and Wolfgang Maier and Jacques Mallet and Sara Marsal and Manuel Mattheisen and Morten Mattingsdal and McCarley, {Robert W.} and Colm McDonald and McIntosh, {Andrew M.} and Sandra Meier and Meijer, {Carin J.} and Bela Melegh and Ingrid Melle and Mesholam-Gately, {Raquelle I.} and Andres Metspalu and Michie, {Patricia T.} and Lili Milani and Vihra Milanova and Younes Mokrab and Morris, {Derek W.} and Ole Mors and Murphy, {Kieran C.} and Murray, {Robin M.} and Inez Myin-Germeys and Bertram M{\"u}ller-Myhsok and Mari Nelis and Igor Nenadic and Nertney, {Deborah A.} and Gerald Nestadt and Nicodemus, {Kristin K.} and Liene Nikitina-Zake and Laura Nisenbaum and Annelie Nordin and Eadbhard O{\textquoteright}Callaghan and Colm O{\textquoteright}Dushlaine and O{\textquoteright}Neill, {F. Anthony} and Sang-Yun Oh and Ann Olincy and Line Olsen and {van Os}, Jim and Christos Pantelis and Papadimitriou, {George N.} and Steixner, {Agnes A.} and Elena Parkhomenko and Pato, {Michele T.} and Tiina Paunio and Milica Pejovic-Milovancevic and Perkins, {Diana O.} and Olli Pietil{\"a}inen and Jonathan Pimm and Pocklington, {Andrew J.} and John Powell and Alkes Price and Pulver, {Ann E.} and Purcell, {Shaun M.} and Digby Quested and Rasmussen, {Henrik B.} and Abraham Reichenberg and Reimers, {Mark A.} and Richards, {Alexander L.} and Roffman, {Joshua L.} and Panos Roussos and Ruderfer, {Douglas M.} and Veikko Salomaa and Sanders, {Alan R.} and Ulrich Schall and Schubert, {Christian R.} and Schulze, {Thomas G.} and Schwab, {Sibylle G.} and Scolnick, {Edward M.} and Scott, {Rodney J.} and Seidman, {Larry J.} and Jianxin Shi and Engilbert Sigurdsson and Teimuraz Silagadze and Silverman, {Jeremy M.} and Kang Sim and Petr Slominsky and Smoller, {Jordan W.} and Hon-Cheong So and Spencer, {Chris C. A.} and Stahl, {Eli A.} and Hreinn Stefansson and Stacy Steinberg and Elisabeth Stogmann and Straub, {Richard E.} and Eric Strengman and Jana Strohmaier and Stroup, {T. Scott} and Mythily Subramaniam and Jaana Suvisaari and Svrakic, {Dragan M.} and Szatkiewicz, {Jin P.} and Erik S{\"o}derman and Srinivas Thirumalai and Draga Toncheva and Tooney, {Paul A.} and Sarah Tosato and Juha Veijola and John Waddington and Dermot Walsh and Dai Wang and Qiang Wang and Webb, {Bradley T.} and Mark Weiser and Wildenauer, {Dieter B.} and Williams, {Nigel M.} and Stephanie Williams and Witt, {Stephanie H.} and Wolen, {Aaron R.} and Wong, {Emily H. M.} and Wormley, {Brandon K.} and Wu, {Jing Qin} and Xi, {Hualin Simon} and Zai, {Clement C.} and Xuebin Zheng and Fritz Zimprich and Wray, {Naomi R.} and Kari Stefansson and Visscher, {Peter M.} and Rolf Adolfsson and Andreassen, {Ole A.} and Blackwood, {Douglas H. 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year = "2020",

month = jun,

day = "25",

doi = "10.1038/s41586-020-2277-x",

language = "English",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

}

Kamitaki, N, Sekar, A, Handsaker, RE, de Rivera, H, Tooley, K, Morris, DL, Taylor, KE, Whelan, CW, Tombleson, P, Loohuis, LMO, Psychosis Endophenotypes International Consortium, Wellcome Trust Case–Control Consortium 2, Psychosis Endophenotype International Consortium, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Boehnke, M, Kimberly, RP, Kaufman, KM, Harley, JB, Langefeld, CD, Seidman, CE, Pato, MT, Pato, CN, Ophoff, RA, Graham, RR, Criswell, LA, Vyse, TJ & McCarroll, SA 2020, 'Complement genes contribute sex-biased vulnerability in diverse disorders', Nature. https://doi.org/10.1038/s41586-020-2277-x

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AU - Sekar, Aswin

AU - Handsaker, Robert E.

AU - de Rivera, Heather

AU - Tooley, Katherine

AU - Morris, David L.

AU - Taylor, Kimberly E.

AU - Whelan, Christopher W.

AU - Tombleson, Philip

AU - Loohuis, Loes M. Olde

AU - Ripke, Stephan

AU - Neale, Benjamin M.

AU - Corvin, Aiden

AU - Walters, James T. R.

AU - Farh, Kai-How

AU - Holmans, Peter A.

AU - Lee, Phil

AU - Bulik-Sullivan, Brendan

AU - Collier, David A.

AU - Huang, Hailiang

AU - Pers, Tune H.

AU - Agartz, Ingrid

AU - Agerbo, Esben

AU - Albus, Margot

AU - Alexander, Madeline

AU - Amin, Farooq

AU - Bacanu, Silviu A.

AU - Begemann, Martin

AU - Belliveau, Richard A.

AU - Bene, Judit

AU - Bergen, Sarah E.

AU - Bevilacqua, Elizabeth

AU - Bigdeli, Tim B.

AU - Black, Donald W.

AU - Bruggeman, Richard

AU - Buccola, Nancy G.

AU - Buckner, Randy L.

AU - Byerley, William

AU - Cahn, Wiepke

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AU - Cairns, Murray J.

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AU - Carrera, Noa

AU - Catts, Stanley V.

AU - Chambert, Kimberly D.

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AU - Chen, Ronald Y. L.

AU - Chen, Eric Y. H.

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AU - Cheung, Eric F. C.

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AU - Cloninger, C. Robert

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AU - Cohen, Nadine

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AU - Craddock, Nick

AU - Crespo-Facorro, Benedicto

AU - Crowley, James J.

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AU - Davis, Kenneth L.

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AU - del Favero, Jurgen

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AU - Demontis, Ditte

AU - Dikeos, Dimitris

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AU - Fanous, Ayman H.

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AU - Freedman, Robert

AU - Freimer, Nelson B.

AU - Friedl, Marion

AU - Friedman, Joseph I.

AU - Fromer, Menachem

AU - Genovese, Giulio

AU - Georgieva, Lyudmila

AU - Gershon, Elliot S.

AU - Giegling, Ina

AU - Giusti-Rodríguez, Paola

AU - Godard, Stephanie

AU - Goldstein, Jacqueline I.

AU - Golimbet, Vera

AU - Gopal, Srihari

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AU - de Haan, Lieuwe

AU - Mitjans, Marina

AU - Hamshere, Marian L.

AU - Hansen, Mark

AU - Hansen, Thomas

AU - Haroutunian, Vahram

AU - Hartmann, Annette M.

AU - Henskens, Frans A.

AU - Herms, Stefan

AU - Hirschhorn, Joel N.

AU - Hoffmann, Per

AU - Hofman, Andrea

AU - Hollegaard, Mads V.

AU - Hougaard, David M.

AU - Ikeda, Masashi

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AU - Keller, Matthew C.

AU - Kelly, Brian J.

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AU - Khrunin, Andrey

AU - Kim, Yunjung

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AU - Li, Tao

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AU - Loughland, Carmel M.

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AU - Magnusson, Patrik K. E.

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AU - Nisenbaum, Laura

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AU - O’Callaghan, Eadbhard

AU - O’Dushlaine, Colm

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AU - Oh, Sang-Yun

AU - Olincy, Ann

AU - Olsen, Line

AU - van Os, Jim

AU - Pantelis, Christos

AU - Papadimitriou, George N.

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AU - Pato, Michele T.

AU - Paunio, Tiina

AU - Pejovic-Milovancevic, Milica

AU - Perkins, Diana O.

AU - Pietiläinen, Olli

AU - Pimm, Jonathan

AU - Pocklington, Andrew J.

AU - Powell, John

AU - Price, Alkes

AU - Pulver, Ann E.

AU - Purcell, Shaun M.

AU - Quested, Digby

AU - Rasmussen, Henrik B.

AU - Reichenberg, Abraham

AU - Reimers, Mark A.

AU - Richards, Alexander L.

AU - Roffman, Joshua L.

AU - Roussos, Panos

AU - Ruderfer, Douglas M.

AU - Salomaa, Veikko

AU - Sanders, Alan R.

AU - Schall, Ulrich

AU - Schubert, Christian R.

AU - Schulze, Thomas G.

AU - Schwab, Sibylle G.

AU - Scolnick, Edward M.

AU - Scott, Rodney J.

AU - Seidman, Larry J.

AU - Shi, Jianxin

AU - Sigurdsson, Engilbert

AU - Silagadze, Teimuraz

AU - Silverman, Jeremy M.

AU - Sim, Kang

AU - Slominsky, Petr

AU - Smoller, Jordan W.

AU - So, Hon-Cheong

AU - Spencer, Chris C. A.

AU - Stahl, Eli A.

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AU - Tosato, Sarah

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AU - Waddington, John

AU - Walsh, Dermot

AU - Wang, Dai

AU - Wang, Qiang

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AU - Weiser, Mark

AU - Wildenauer, Dieter B.

AU - Williams, Nigel M.

AU - Williams, Stephanie

AU - Witt, Stephanie H.

AU - Wolen, Aaron R.

AU - Wong, Emily H. M.

AU - Wormley, Brandon K.

AU - Wu, Jing Qin

AU - Xi, Hualin Simon

AU - Zai, Clement C.

AU - Zheng, Xuebin

AU - Zimprich, Fritz

AU - Wray, Naomi R.

AU - Stefansson, Kari

AU - Visscher, Peter M.

AU - Adolfsson, Rolf

AU - Andreassen, Ole A.

AU - Blackwood, Douglas H. R.

AU - Bramon, Elvira

AU - Buxbaum, Joseph D.

AU - Børglum, Anders D.

AU - Cichon, Sven

AU - Darvasi, Ariel

AU - Domenici, Enrico

AU - Ehrenreich, Hannelore

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AU - Gejman, Pablo V.

AU - Gill, Michael

AU - Gurling, Hugh

AU - Hultman, Christina M.

AU - Iwata, Nakao

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AU - Jönsson, Erik G.

AU - Kendler, Kenneth S.

AU - Kirov, George

AU - Knight, Jo

AU - Lencz, Todd

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AU - Li, Qingqin S.

AU - Liu, Jianjun

AU - Malhotra, Anil K.

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AU - Mortensen, Preben B.

AU - Mowry, Bryan J.

AU - Nöthen, Markus M.

AU - Ophoff, Roel A.

AU - Owen, Michael J.

AU - Palotie, Aarno

AU - Pato, Carlos N.

AU - Petryshen, Tracey L.

AU - Psychosis Endophenotypes International Consortium

AU - Posthuma, Danielle

AU - Rietschel, Marcella

AU - Riley, Brien P.

AU - Dan Rujescu, null

AU - Sham, Pak C.

AU - Sklar, Pamela

AU - Wellcome Trust Case–Control Consortium 2

AU - Clair, David St

AU - Psychosis Endophenotype International Consortium

AU - Weinberger, Daniel R.

AU - Wendland, Jens R.

AU - Werge, Thomas

AU - Daly, Mark J.

AU - Sullivan, Patrick F.

AU - O’Donovan, Michael C.

AU - Schizophrenia Working Group of the Psychiatric Genomics Consortium

AU - Boehnke, Michael

AU - Kimberly, Robert P.

AU - Kaufman, Kenneth M.

AU - Harley, John B.

AU - Langefeld, Carl D.

AU - Seidman, Christine E.

AU - Pato, Michele T.

AU - Pato, Carlos N.

AU - Ophoff, Roel A.

AU - Graham, Robert R.

AU - Criswell, Lindsey A.

AU - Vyse, Timothy J.

AU - McCarroll, Steven A.

AU - Lin, Kuang

AU - Linszen, Don H.

AU - Mata, Ignacio

AU - McIntosh, Andrew M.

AU - Murray, Robin M.

AU - Ophoff, Roel A.

AU - van Os, Jim

AU - Powell, John

AU - Rujescu, Dan

AU - Walshe, Muriel

AU - Weisbrod, Matthias

AU - Wiersma, Durk

AU - Donnelly, Peter

AU - Barroso, Ines

AU - Blackwell, Jenefer M.

AU - Bramon, Elvira

AU - Brown, Matthew A.

AU - Casas, Juan P.

AU - Corvin, Aiden

AU - Deloukas, Panos

AU - Duncanson, Audrey

AU - Jankowski, Janusz

AU - Markus, Hugh S.

AU - Mathew, Christopher G.

AU - Palmer, Colin N. A.

AU - Plomin, Robert

AU - Rautanen, Anna

AU - Sawcer, Stephen J.

AU - Trembath, Richard C.

AU - Viswanathan, Ananth C.

AU - Wood, Nicholas W.

AU - Spencer, Chris C. A.

AU - Band, Gavin

AU - Bellenguez, C. line

AU - Donnelly, Peter

AU - Freeman, Colin

AU - Giannoulatou, Eleni

AU - Hellenthal, Garrett

AU - Pearson, Richard

AU - Pirinen, Matti

AU - Strange, Amy

AU - Su, Zhan

AU - Vukcevic, Damjan

AU - Langford, Cordelia

AU - Barroso, Ines

AU - Blackburn, Hannah

AU - Bumpstead, Suzannah J.

AU - Deloukas, Panos

AU - Dronov, Serge

AU - Edkins, Sarah

AU - Gillman, Matthew

AU - Gray, Emma

AU - Gwilliam, Rhian

AU - Hammond, Naomi

AU - Hunt, Sarah E.

AU - Jayakumar, Alagurevathi

AU - Liddle, Jennifer

AU - McCann, Owen T.

AU - Potter, Simon C.

AU - Ravindrarajah, Radhi

AU - Ricketts, Michelle

AU - Tashakkori-Ghanbaria, Avazeh

AU - Waller, Matthew

AU - Weston, Paul

AU - Whittaker, Pamela

AU - Widaa, Sara

AU - Mathew, Christopher G.

AU - Blackwell, Jenefer M.

AU - Brown, Matthew A.

AU - Corvin, Aiden

AU - McCarthy, Mark I.

AU - Spencer, Chris C. A.

PY - 2020/6/25

Y1 - 2020/6/25

N2 - Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3–6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren’s syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

AB - Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren’s syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3–6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren’s syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren’s syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s syndrome and men’s greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85086580754&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/32499649

U2 - 10.1038/s41586-020-2277-x

DO - 10.1038/s41586-020-2277-x

M3 - Article

C2 - 32499649

JO - Nature

JF - Nature

SN - 0028-0836

ER -

Complement genes contribute sex-biased vulnerability in diverse disorders

Abstract

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