TY - JOUR
T1 - Complement genes contribute sex-biased vulnerability in diverse disorders
AU - Kamitaki, Nolan
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
AU - Cai, Guiqing
AU - Cairns, Murray J.
AU - Campion, Dominique
AU - Cantor, Rita M.
AU - Carr, Vaughan J.
AU - Carrera, Noa
AU - Catts, Stanley V.
AU - Chambert, Kimberly D.
AU - Chan, Raymond C.K.
AU - Chen, Ronald Y.L.
AU - Chen, Eric Y.H.
AU - Cheng, Wei
AU - Cheung, Eric F.C.
AU - Chong, Siow Ann
AU - Cloninger, C. Robert
AU - Cohen, David
AU - Cohen, Nadine
AU - Cormican, Paul
AU - Craddock, Nick
AU - Crespo-Facorro, Benedicto
AU - Crowley, James J.
AU - Curtis, David
AU - Davidson, Michael
AU - Davis, Kenneth L.
AU - Degenhardt, Franziska
AU - Del Favero, Jurgen
AU - DeLisi, Lynn E.
AU - Demontis, Ditte
AU - Dikeos, Dimitris
AU - Dinan, Timothy
AU - Djurovic, Srdjan
AU - Donohoe, Gary
AU - Drapeau, Elodie
AU - Duan, Jubao
AU - Dudbridge, Frank
AU - Durmishi, Naser
AU - Eichhammer, Peter
AU - Eriksson, Johan
AU - Escott-Price, Valentina
AU - Essioux, Laurent
AU - Fanous, Ayman H.
AU - Farrell, Martilias S.
AU - Frank, Josef
AU - Franke, Lude
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
AU - Gratten, Jacob
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
AU - Joa, Inge
AU - Julià, Antonio
AU - Kahn, René S.
AU - Kalaydjieva, Luba
AU - Karachanak-Yankova, Sena
AU - Karjalainen, Juha
AU - Kavanagh, David
AU - Keller, Matthew C.
AU - Kelly, Brian J.
AU - Kennedy, James L.
AU - Khrunin, Andrey
AU - Kim, Yunjung
AU - Klovins, Janis
AU - Knowles, James A.
AU - Konte, Bettina
AU - Kucinskas, Vaidutis
AU - Kucinskiene, Zita Ausrele
AU - Kuzelova-Ptackova, Hana
AU - Kähler, Anna K.
AU - Laurent, Claudine
AU - Keong, Jimmy Lee Chee
AU - Lee, S. Hong
AU - Legge, Sophie E.
AU - Lerer, Bernard
AU - Li, Miaoxin
AU - Li, Tao
AU - Liang, Kung Yee
AU - Lieberman, Jeffrey
AU - Limborska, Svetlana
AU - Loughland, Carmel M.
AU - Jan Lubinski, Lubinski
AU - Lönnqvist, Jouko
AU - Macek, Milan
AU - Magnusson, Patrik K.E.
AU - Maher, Brion S.
AU - Maier, Wolfgang
AU - Mallet, Jacques
AU - Marsal, Sara
AU - Mattheisen, Manuel
AU - Mattingsdal, Morten
AU - McCarley, Robert W.
AU - McDonald, Colm
AU - McIntosh, Andrew M.
AU - Meier, Sandra
AU - Meijer, Carin J.
AU - Melegh, Bela
AU - Melle, Ingrid
AU - Mesholam-Gately, Raquelle I.
AU - Metspalu, Andres
AU - Michie, Patricia T.
AU - Milani, Lili
AU - Milanova, Vihra
AU - Mokrab, Younes
AU - Morris, Derek W.
AU - Mors, Ole
AU - Murphy, Kieran C.
AU - Murray, Robin M.
AU - Myin-Germeys, Inez
AU - Müller-Myhsok, Bertram
AU - Nelis, Mari
AU - Nenadic, Igor
AU - Nertney, Deborah A.
AU - Nestadt, Gerald
AU - Nicodemus, Kristin K.
AU - Nikitina-Zake, Liene
AU - Nisenbaum, Laura
AU - Nordin, Annelie
AU - O’Callaghan, Eadbhard
AU - O’Dushlaine, Colm
AU - O’Neill, F. Anthony
AU - Oh, Sang Yun
AU - Olincy, Ann
AU - Olsen, Line
AU - Van Os, Jim
AU - Pantelis, Christos
AU - Papadimitriou, George N.
AU - Steixner, Agnes A.
AU - Parkhomenko, Elena
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.
AU - Stefansson, Hreinn
AU - Steinberg, Stacy
AU - Stogmann, Elisabeth
AU - Straub, Richard E.
AU - Strengman, Eric
AU - Strohmaier, Jana
AU - Stroup, T. Scott
AU - Subramaniam, Mythily
AU - Suvisaari, Jaana
AU - Svrakic, Dragan M.
AU - Szatkiewicz, Jin P.
AU - Söderman, Erik
AU - Thirumalai, Srinivas
AU - Toncheva, Draga
AU - Tooney, Paul A.
AU - Tosato, Sarah
AU - Veijola, Juha
AU - Waddington, John
AU - Walsh, Dermot
AU - Wang, Dai
AU - Wang, Qiang
AU - Webb, Bradley T.
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
AU - Esko, Tõnu
AU - Gejman, Pablo V.
AU - Gill, Michael
AU - Gurling, Hugh
AU - Hultman, Christina M.
AU - Iwata, Nakao
AU - Jablensky, Assen V.
AU - Jönsson, Erik G.
AU - Kendler, Kenneth S.
AU - Kirov, George
AU - Knight, Jo
AU - Lencz, Todd
AU - Levinson, Douglas F.
AU - Li, Qingqin S.
AU - Liu, Jianjun
AU - Malhotra, Anil K.
AU - McCarroll, Steven A.
AU - McQuillin, Andrew
AU - Moran, Jennifer L.
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 - Posthuma, Danielle
AU - Rietschel, Marcella
AU - Riley, Brien P.
AU - Rujescu, Dan
AU - Sham, Pak C.
AU - Sklar, Pamela
AU - Clair, David St
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 - Arranz, Maria J.
AU - Bakker, Steven
AU - Bender, Stephan
AU - Bramon, Elvira
AU - Collier, David A.
AU - Crespo-Facorro, Benedicto
AU - Hall, Jeremy
AU - Iyegbe, Conrad
AU - Jablensky, Assen V.
AU - Kahn, René S.
AU - Kalaydjieva, Luba
AU - Lawrie, Stephen
AU - Lewis, Cathryn M.
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, Céline
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.
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 - Schizophrenia Working Group of the Psychiatric Genomics Consortium
AU - Psychosis Endophenotypes International Consortium
AU - Wellcome Trust Case–Control Consortium 2
N1 - Funding Information:
Acknowledgements This work was supported by the National Human Genome Research Institute (HG006855), the National Institute of Mental Health (MH112491, MH105641, MH105653), the Stanley Center for Psychiatric Research, and the National Institute for Health Research Biomedical Research Centre (NIHR BRC) at Guy’s and St Thomas’ NHS Foundation and King’s College London. We thank C. Usher and C. Patil for contributions to the figures and manuscript text, and M. Florio for suggestions regarding figure display.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
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.
KW - Adult
KW - Alleles
KW - Complement C3/analysis
KW - Complement C4/analysis
KW - Female
KW - Genetic Predisposition to Disease
KW - HLA Antigens/genetics
KW - Haplotypes
KW - Humans
KW - Lupus Erythematosus, Systemic/blood
KW - Major Histocompatibility Complex/genetics
KW - Male
KW - Middle Aged
KW - Sex Characteristics
KW - Sjogren's Syndrome/blood
KW - Young Adult
UR - https://www.scopus.com/pages/publications/85086580754
UR - https://www.scopus.com/inward/citedby.url?scp=85086580754&partnerID=8YFLogxK
U2 - 10.1038/s41586-020-2277-x
DO - 10.1038/s41586-020-2277-x
M3 - Article
C2 - 32499649
SN - 0028-0836
VL - 582
SP - 577
EP - 581
JO - Nature
JF - Nature
IS - 7813
ER -
