Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Complement genes contribute sex-biased vulnerability in diverse disorders

Nature volume 582, pages 577–581 (2020)Cite this article

Subjects

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 locus3,4,5,6. 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Association of SLE and Sjögren’s syndrome with C4 alleles.
Fig. 2: C4 and trans-ancestral analysis of the MHC-association signal in SLE.
Fig. 3: Sex differences in the magnitude of C4 genetic effects and complement protein concentrations.

Similar content being viewed by others

Data availability

Individual genotype data for Sjögren’s syndrome cases and controls and individual plasma concentrations for C4 and C3 are available in dbGaP under accession number phs000672.v1.p1. Individual genotype data for schizophrenia cases and controls are available by application to the Psychiatric Genomics Consortium (PGC). Questions regarding individual genotype data for SLE cases and controls of European and/or African American ancestry can be directed to T.J.V. Data resources are available on the McCarroll lab website at http://mccarrolllab.org/resources/resources-for-c4/. We have deposited the haplotype reference panel we created for C4 imputation in dbGaP under accession number phs001992.v1.p1. Genotype and protein concentration data for CSF samples are available upon request.

Code availability

Software scripts and instructions for imputing C4 alleles into SNP datasets are available on the McCarroll laboratory website at http://mccarrolllab.org/resources/resources-for-c4/.

References

  1. Ngo, S. T., Steyn, F. J. & McCombe, P. A. Gender differences in autoimmune disease. Front. Neuroendocrinol. 35, 347–369 (2014).

    CAS  PubMed  Google Scholar 

  2. Abel, K. M., Drake, R. & Goldstein, J. M. Sex differences in schizophrenia. Int. Rev. Psychiatry 22, 417–428 (2010).

    PubMed  Google Scholar 

  3. Langefeld, C. D. et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat. Commun. 8, 16021 (2017).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rioux, J. D. et al. Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases. Proc. Natl Acad. Sci. USA 106, 18680–18685 (2009).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hanscombe, K. B. et al. Genetic fine mapping of systemic lupus erythematosus MHC associations in Europeans and African Americans. Hum. Mol. Genet. 27, 3813–3824 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Cruz-Tapias, P., Rojas-Villarraga, A., Maier-Moore, S. & Anaya, J. M. HLA and Sjögren’s syndrome susceptibility. a meta-analysis of worldwide studies. Autoimmun. Rev. 11, 281–287 (2012).

    CAS  PubMed  Google Scholar 

  7. Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Gaya da Costa, M. et al. Age and sex-associated changes of complement activity and complement levels in a healthy Caucasian population. Front. Immunol. 9, 2664 (2018).

    PubMed  PubMed Central  Google Scholar 

  9. Ritchie, R. F. et al. Reference distributions for complement proteins C3 and C4: a practical, simple and clinically relevant approach in a large cohort. J. Clin. Lab. Anal. 18, 1–8 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lawrence, J. S., Martins, C. L. & Drake, G. L. A family survey of lupus erythematosus. 1. Heritability. J. Rheumatol. 14, 913–921 (1987).

    CAS  PubMed  Google Scholar 

  11. Lipsky, P. E. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat. Immunol. 2, 764–766 (2001).

    CAS  PubMed  Google Scholar 

  12. Ippolito, A. et al. Autoantibodies in systemic lupus erythematosus: comparison of historical and current assessment of seropositivity. Lupus 20, 250–255 (2011).

    CAS  PubMed  Google Scholar 

  13. Lee, K. H., Wucherpfennig, K. W. & Wiley, D. C. Structure of a human insulin peptide–HLA–DQ8 complex and susceptibility to type 1 diabetes. Nat. Immunol. 2, 501–507 (2001).

    CAS  PubMed  Google Scholar 

  14. Raychaudhuri, S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Morris, D. L. et al. MHC associations with clinical and autoantibody manifestations in European SLE. Genes Immun. 15, 210–217 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Bánlaki, Z., Doleschall, M., Rajczy, K., Fust, G. & Szilágyi, A. Fine-tuned characterization of RCCX copy number variants and their relationship with extended MHC haplotypes. Genes Immun. 13, 530–535 (2012).

    PubMed  Google Scholar 

  17. Isenman, D. E. & Young, J. R. The molecular basis for the difference in immune hemolysis activity of the Chido and Rodgers isotypes of human complement component C4. J. Immunol. 132, 3019–3027 (1984).

    CAS  PubMed  Google Scholar 

  18. Law, S. K., Dodds, A. W. & Porter, R. R. A comparison of the properties of two classes, C4A and C4B, of the human complement component C4. EMBO J. 3, 1819–1823 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Birmingham, D. J. et al. The complex nature of serum C3 and C4 as biomarkers of lupus renal flare. Lupus 19, 1272–1280 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Ross, S. C. & Densen, P. Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. Medicine 63, 243–273 (1984).

    CAS  PubMed  Google Scholar 

  21. Wu, Y. L., Hauptmann, G., Viguier, M. & Yu, C. Y. Molecular basis of complete complement C4 deficiency in two North-African families with systemic lupus erythematosus. Genes Immun. 10, 433–445 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. International Consortium for Systemic Lupus Erythematosus. Genome-wide association scan in women with systemic lupus erythematosus identifies susceptibility variants in ITGAM, PXK, KIAA1542 and other loci. Nat. Genet. 40, 204–210 (2008).

    Google Scholar 

  23. Yang, Y. et al. Gene copy-number variation and associated polymorphisms of complement component C4 in human systemic lupus erythematosus (SLE): low copy number is a risk factor for and high copy number is a protective factor against SLE susceptibility in European Americans. Am. J. Hum. Genet. 80, 1037–1054 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Jüptner, M. et al. Low copy numbers of complement C4 and homozygous deficiency of C4A may predispose to severe disease and earlier disease onset in patients with systemic lupus erythematosus. Lupus 27, 600–609 (2018).

    PubMed  Google Scholar 

  25. Boteva, L. et al. Genetically determined partial complement C4 deficiency states are not independent risk factors for SLE in UK and Spanish populations. Am. J. Hum. Genet. 90, 445–456 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Pato, M. T. et al. The genomic psychiatry cohort: partners in discovery. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 162, 306–312 (2013).

    Google Scholar 

  27. Sanders, S. J. et al. Whole genome sequencing in psychiatric disorders: the WGSPD consortium. Nat. Neurosci. 20, 1661–1668 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kuo, C. F. et al. Familial risk of Sjögren’s syndrome and co-aggregation of autoimmune diseases in affected families: a nationwide population study. Arthritis Rheumatol. 67, 1904–1912 (2015).

    PubMed  PubMed Central  Google Scholar 

  29. Fayyaz, A., Kurien, B. T. & Scofield, R. H. Autoantibodies in Sjögren’s Syndrome. Rheum. Dis. Clin. North Am. 42, 419–434 (2016).

    PubMed  PubMed Central  Google Scholar 

  30. Ramos-Casals, M. et al. Hypocomplementaemia as an immunological marker of morbidity and mortality in patients with primary Sjögren’s syndrome. Rheumatology 44, 89–94 (2005).

    CAS  PubMed  Google Scholar 

  31. Chused, T. M., Kassan, S. S., Opelz, G., Moutsopoulos, H. M. & Terasaki, P. I. Sjögren’s syndrome association with HLA-Dw3. N. Engl. J. Med. 296, 895–897 (1977).

    CAS  PubMed  Google Scholar 

  32. Taylor, K. E. et al. Genome-wide association analysis reveals genetic heterogeneity of Sjögren’s syndrome according to ancestry. Arthritis Rheumatol. 69, 1294–1305 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Khramtsova, E. A., Davis, L. K. & Stranger, B. E. The role of sex in the genomics of human complex traits. Nat. Rev. Genet. 20, 173–190 (2019).

    CAS  PubMed  Google Scholar 

  34. Hughes, T. et al. Analysis of autosomal genes reveals gene–sex interactions and higher total genetic risk in men with systemic lupus erythematosus. Ann. Rheum. Dis. 71, 694–699 (2012).

    CAS  PubMed  Google Scholar 

  35. GTEx Consortium. Genetic effects on gene expression across human tissues. Nature 550, 204–213 (2017).

    PubMed Central  Google Scholar 

  36. Brinks, R. et al. Age-specific and sex-specific incidence of systemic lupus erythematosus: an estimate from cross-sectional claims data of 2.3 million people in the German statutory health insurance 2002. Lupus Sci. Med. 3, e000181 (2016).

    PubMed  PubMed Central  Google Scholar 

  37. Kim, H. J. et al. Incidence, mortality, and causes of death in physician-diagnosed primary Sjögren’s syndrome in Korea: A nationwide, population-based study. Semin. Arthritis Rheum. 47, 222–227 (2017).

    PubMed  Google Scholar 

  38. Degn, S. E. et al. Clonal evolution of autoreactive germinal centers. Cell 170, 913–926 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Estrada, K. et al. A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica. Nat. Commun. 9, 1929 (2018).

    ADS  PubMed  PubMed Central  Google Scholar 

  40. Pittock, S. J. et al. Neuromyelitis optica and non organ-specific autoimmunity. Arch. Neurol. 65, 78–83 (2008).

    PubMed  Google Scholar 

  41. Erdei, A. et al. Expression and role of CR1 and CR2 on B and T lymphocytes under physiological and autoimmune conditions. Mol. Immunol. 46, 2767–2773 (2009).

    CAS  PubMed  Google Scholar 

  42. Unterman, A. et al. Neuropsychiatric syndromes in systemic lupus erythematosus: a meta-analysis. Semin. Arthritis Rheum. 41, 1–11 (2011).

    PubMed  Google Scholar 

  43. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).

    ADS  PubMed Central  Google Scholar 

  44. Handsaker, R. E. et al. Large multiallelic copy number variations in humans. Nat. Genet. 47, 296–303 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Browning, S. R. & Browning, B. L. Rapid and accurate haplotype phasing and missing-data inference for whole-genome association studies by use of localized haplotype clustering. Am. J. Hum. Genet. 81, 1084–1097 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Browning, B. L. & Browning, S. R. Genotype imputation with millions of reference samples. Am. J. Hum. Genet. 98, 116–126 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Zheng, X. et al. HIBAG—HLA genotype imputation with attribute bagging. Pharmacogenomics J. 14, 192–200 (2014).

    CAS  PubMed  Google Scholar 

  48. Zheng, X. Imputation-based HLA typing with SNPs in GWAS studies. Methods Mol. Biol. 1802, 163–176 (2018).

    CAS  PubMed  Google Scholar 

  49. Luykx, J. J. et al. A common variant in ERBB4 regulates GABA concentrations in human cerebrospinal fluid. Neuropsychopharmacology 37, 2088–2092 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Albersen, M. et al. Vitamin B-6 vitamers in human plasma and cerebrospinal fluid. Am. J. Clin. Nutr. 100, 587–592 (2014).

    CAS  PubMed  Google Scholar 

  51. Malladi, A. S. et al. Primary Sjögren’s syndrome as a systemic disease: a study of participants enrolled in an international Sjögren’s syndrome registry. Arthritis Care Res. (Hoboken) 64, 911–918 (2012).

    Google Scholar 

  52. The ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 489, 57–74 (2012).

    ADS  PubMed Central  Google Scholar 

  53. Kent, W. J. et al. The human genome browser at UCSC. Genome Res. 12, 996–1006 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

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.

Author information

Author notes

  1. A list of participants and their affiliations appears in the online version of the paper

Authors and Affiliations

  1. Department of Genetics, Harvard Medical School, Boston, MA, USA

    Nolan Kamitaki, Aswin Sekar, Robert E. Handsaker, Heather de Rivera, Katherine Tooley, Christopher W. Whelan, Christine E. Seidman & Steven A. McCarroll

  2. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Nolan Kamitaki, Aswin Sekar, Robert E. Handsaker, Heather de Rivera, Katherine Tooley, Christopher W. Whelan & Steven A. McCarroll

  3. Department of Medical and Molecular Genetics, King’s College London, London, UK

    David L. Morris, Philip Tombleson & Timothy J. Vyse

  4. Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, Division of Rheumatology, UCSF School of Medicine, San Francisco, CA, USA

    Kimberly E. Taylor & Lindsey A. Criswell

  5. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    Loes M. Olde Loohuis & Roel A. Ophoff

  6. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA

    Loes M. Olde Loohuis & Roel A. Ophoff

  7. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA

    Michael Boehnke

  8. Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA

    Robert P. Kimberly

  9. Center for Autoimmune Genomics and Etiology (CAGE), Department of Pediatrics, Cincinnati Children’s Medical Center & University of Cincinnati and the US Department of Veterans Affairs Medical Center, Cincinnati, OH, USA

    Kenneth M. Kaufman & John B. Harley

  10. Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston–Salem, NC, USA

    Carl D. Langefeld

  11. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    Christine E. Seidman

  12. Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA

    Christine E. Seidman

  13. SUNY Downstate Medical Center, Brooklyn, NY, USA

    Michele T. Pato & Carlos N. Pato

  14. Human Genetics, Genentech, South San Francisco, CA, USA

    Robert R. Graham

  15. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    Stephan Ripke, Benjamin M. Neale, Kai-How Farh, Phil Lee, Brendan Bulik-Sullivan, Hailiang Huang, Menachem Fromer, Jacqueline I. Goldstein & Mark J. Daly

  16. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Stephan Ripke, Benjamin M. Neale, Phil Lee, Brendan Bulik-Sullivan, Richard A. Belliveau Jr, Sarah E. Bergen, Elizabeth Bevilacqua, Kimberly D. Chambert, Menachem Fromer, Giulio Genovese, Colm O’Dushlaine, Edward M. Scolnick, Jordan W. Smoller, Steven A. McCarroll, Jennifer L. Moran, Aarno Palotie, Tracey L. Petryshen & Mark J. Daly

  17. Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Benjamin M. Neale, Hailiang Huang, Tune H. Pers, Jacqueline I. Goldstein, Joel N. Hirschhorn, Alkes Price, Eli A. Stahl, Tõnu Esko & Mark J. Daly

  18. Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    Benjamin M. Neale, Phil Lee, Menachem Fromer, Jordan W. Smoller & Aarno Palotie

  19. Neuropsychiatric Genetics Research Group, Department of Psychiatry, Trinity College Dublin, Dublin, Ireland

    Aiden Corvin, Paul Cormican, Gary Donohoe, Derek W. Morris, Michael Gill, Aiden Corvin & Aiden Corvin

  20. MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, School of Medicine, Cardiff University, Cardiff, UK

    James T. R. Walters, Peter A. Holmans, Noa Carrera, Nick Craddock, Valentina Escott-Price, Lyudmila Georgieva, Marian L. Hamshere, David Kavanagh, Sophie E. Legge, Andrew J. Pocklington, Alexander L. Richards, Douglas M. Ruderfer, Nigel M. Williams, George Kirov, Michael J. Owen & Michael C. O’Donovan

  21. National Centre for Mental Health, Cardiff University, Cardiff, UK

    Peter A. Holmans, Nick Craddock, Michael J. Owen & Michael C. O’Donovan

  22. Eli Lilly, Windlesham, UK

    David A. Collier, Younes Mokrab & David A. Collier

  23. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London, UK

    David A. Collier, David A. Collier & Robert Plomin

  24. Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark

    Tune H. Pers

  25. Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, USA

    Tune H. Pers, Joel N. Hirschhorn & Tõnu Esko

  26. Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Stockholm, Sweden

    Ingrid Agartz, Erik Söderman & Erik G. Jönsson

  27. Department of Psychiatry, Diakonhjemmet Hospital, Oslo, Norway

    Ingrid Agartz

  28. NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Ingrid Agartz, Srdjan Djurovic, Morten Mattingsdal, Ingrid Melle, Ole A. Andreassen & Erik G. Jönsson

  29. Centre for Integrative Register-based Research, CIRRAU, Aarhus University, Aarhus, Denmark

    Esben Agerbo & Preben B. Mortensen

  30. National Centre for Register-based Research, Aarhus University, Aarhus, Denmark

    Esben Agerbo & Preben B. Mortensen

  31. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark

    Esben Agerbo, Ditte Demontis, Thomas Hansen, Manuel Mattheisen, Ole Mors, Line Olsen, Henrik B. Rasmussen, Anders D. Børglum, Preben B. Mortensen & Thomas Werge

  32. State Mental Hospital, Haar, Germany

    Margot Albus

  33. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

    Madeline Alexander, Claudine Laurent & Douglas F. Levinson

  34. Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs Medical Center, Atlanta, GA, USA

    Farooq Amin

  35. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA

    Farooq Amin

  36. Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA

    Silviu A. Bacanu, Tim B. Bigdeli, Bradley T. Webb & Brandon K. Wormley

  37. Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany

    Martin Begemann, Marina Mitjans, Agnes A. Steixner & Hannelore Ehrenreich

  38. Department of Medical Genetics, University of Pécs, Pécs, Hungary

    Judit Bene & Bela Melegh

  39. Szentagothai Research Center, University of Pécs, Pécs, Hungary

    Judit Bene & Bela Melegh

  40. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Sarah E. Bergen, Anna K. Kähler, Patrik K. E. Magnusson, Christina M. Hultman & Patrick F. Sullivan

  41. Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA

    Donald W. Black

  42. Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Richard Bruggeman

  43. School of Nursing, Louisiana State University Health Sciences Center, New Orleans, LA, USA

    Nancy G. Buccola

  44. Athinoula A. Martinos Center, Massachusetts General Hospital, Boston, MA, USA

    Randy L. Buckner & Joshua L. Roffman

  45. Center for Brain Science, Harvard University, Cambridge, MA, USA

    Randy L. Buckner

  46. Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    Randy L. Buckner & Joshua L. Roffman

  47. Department of Psychiatry, University of California at San Francisco, San Francisco, CA, USA

    William Byerley

  48. Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands

    Wiepke Cahn, René S. Kahn, Eric Strengman, Roel A. Ophoff, Steven Bakker & René S. Kahn

  49. Department of Human Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Guiqing Cai & Joseph D. Buxbaum

  50. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Guiqing Cai, Kenneth L. Davis, Elodie Drapeau, Joseph I. Friedman, Vahram Haroutunian, Elena Parkhomenko, Abraham Reichenberg, Jeremy M. Silverman & Joseph D. Buxbaum

  51. Schizophrenia Research Institute, Sydney, New South Wales, Australia

    Murray J. Cairns, Vaughan J. Carr, Stanley V. Catts, Frans A. Henskens, Carmel M. Loughland, Patricia T. Michie, Christos Pantelis, Ulrich Schall, Rodney J. Scott, Paul A. Tooney, Jing Qin Wu & Assen V. Jablensky

  52. Priority Centre for Translational Neuroscience and Mental Health, University of Newcastle, Newcastle, New South Wales, Australia

    Murray J. Cairns, Brian J. Kelly, Carmel M. Loughland, Ulrich Schall & Paul A. Tooney

  53. School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, New South Wales, Australia

    Murray J. Cairns, Rodney J. Scott, Paul A. Tooney & Jing Qin Wu

  54. Centre Hospitalier du Rouvray and INSERM U1079 Faculty of Medicine, Rouen, France

    Dominique Campion

  55. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA

    Rita M. Cantor & Roel A. Ophoff

  56. School of Psychiatry, University of New South Wales, Sydney, New South Wales, Australia

    Vaughan J. Carr

  57. Royal Brisbane and Women’s Hospital, University of Queensland, Brisbane, Australia

    Stanley V. Catts

  58. Institute of Psychology, Chinese Academy of Science, Beijing, China

    Raymond C. K. Chan

  59. Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

    Ronald Y. L. Chen, Eric Y. H. Chen, Miaoxin Li, Hon-Cheong So, Emily H. M. Wong & Pak C. Sham

  60. State Key Laboratory for Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

    Eric Y. H. Chen, Miaoxin Li & Pak C. Sham

  61. Department of Computer Science, University of North Carolina, Chapel Hill, NC, USA

    Wei Cheng

  62. Castle Peak Hospital, Hong Kong, China

    Eric F. C. Cheung

  63. Institute of Mental Health, Singapore, Singapore

    Siow Ann Chong, Jimmy Lee Chee Keong, Kang Sim & Mythily Subramaniam

  64. Department of Psychiatry, Washington University, St Louis, MO, USA

    C. Robert Cloninger & Dragan M. Svrakic

  65. Department of Child and Adolescent Psychiatry, Assistance Publique Hopitaux de Paris, Pierre and Marie Curie Faculty of Medicine and Institute for Intelligent Systems and Robotics, Paris, France

    David Cohen

  66. Blue Note Biosciences, Princeton, NJ, USA

    Nadine Cohen

  67. University Hospital Marqués de Valdecilla, Instituto de Formación e Investigación Marqués de Valdecilla, University of Cantabria, Santander, Spain

    Benedicto Crespo-Facorro

  68. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    James J. Crowley, Martilias S. Farrell, Paola Giusti-Rodríguez, Yunjung Kim, Jin P. Szatkiewicz, Stephanie Williams & Patrick F. Sullivan

  69. Department of Psychological Medicine, Queen Mary University of London, London, UK

    David Curtis

  70. Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK

    David Curtis, Jonathan Pimm, Hugh Gurling & Andrew McQuillin

  71. Sheba Medical Center, Tel Hashomer, Israel

    Michael Davidson & Mark Weiser

  72. Department of Genomics, Life and Brain Center, Bonn, Germany

    Franziska Degenhardt, Stefan Herms, Per Hoffmann, Andrea Hofman, Sven Cichon & Markus M. Nöthen

  73. Institute of Human Genetics, University of Bonn, Bonn, Germany

    Franziska Degenhardt, Stefan Herms, Per Hoffmann, Andrea Hofman, Sven Cichon & Markus M. Nöthen

  74. Applied Molecular Genomics Unit, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium

    Jurgen Del Favero

  75. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Lynn E. DeLisi, Robert W. McCarley, Raquelle I. Mesholam-Gately, Larry J. Seidman & Tracey L. Petryshen

  76. VA Boston Health Care System, Brockton, MA, USA

    Lynn E. DeLisi & Robert W. McCarley

  77. Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark

    Ditte Demontis, Manuel Mattheisen, Ole Mors & Anders D. Børglum

  78. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Ditte Demontis, Manuel Mattheisen & Anders D. Børglum

  79. First Department of Psychiatry, University of Athens Medical School, Athens, Greece

    Dimitris Dikeos & George N. Papadimitriou

  80. Department of Psychiatry, University College Cork, Cork, Ireland

    Timothy Dinan

  81. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

    Srdjan Djurovic

  82. Cognitive Genetics and Therapy Group, School of Psychology and Discipline of Biochemistry, National University of Ireland Galway, Galway, Ireland

    Gary Donohoe & Derek W. Morris

  83. Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA

    Jubao Duan, Alan R. Sanders & Pablo V. Gejman

  84. Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL, USA

    Jubao Duan, Alan R. Sanders & Pablo V. Gejman

  85. Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK

    Frank Dudbridge

  86. Department of Child and Adolescent Psychiatry, University Clinic of Psychiatry, Skopje, Republic of Macedonia

    Naser Durmishi

  87. Department of Psychiatry, University of Regensburg, Regensburg, Germany

    Peter Eichhammer

  88. Department of General Practice, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland

    Johan Eriksson

  89. Folkhälsan Research Center, Helsinki, Finland, Biomedicum Helsinki 1, Helsinki, Finland

    Johan Eriksson

  90. National Institute for Health and Welfare, Helsinki, Finland

    Johan Eriksson & Veikko Salomaa

  91. Translational Technologies and Bioinformatics, Pharma Research and Early Development, F. Hoffman-La Roche, Switzerland

    Laurent Essioux

  92. Department of Psychiatry, Georgetown University School of Medicine, Washington, DC, USA

    Ayman H. Fanous

  93. Department of Psychiatry, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA

    Ayman H. Fanous

  94. Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, USA

    Ayman H. Fanous

  95. Mental Health Service Line, Washington VA Medical Center, Washington, DC, USA

    Ayman H. Fanous

  96. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany

    Josef Frank, Sandra Meier, Thomas G. Schulze, Jana Strohmaier, Stephanie H. Witt & Marcella Rietschel

  97. Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands

    Lude Franke & Juha Karjalainen

  98. Department of Psychiatry, University of Colorado Denver, Aurora, CO, USA

    Robert Freedman & Ann Olincy

  99. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA, USA

    Nelson B. Freimer, Roel A. Ophoff & Roel A. Ophoff

  100. Department of Psychiatry, University of Halle, Halle, Germany

    Marion Friedl, Ina Giegling, Annette M. Hartmann, Bettina Konte,  Dan Rujescu & Dan Rujescu

  101. Division of Psychiatric Genomics, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Menachem Fromer, Shaun M. Purcell, Panos Roussos, Douglas M. Ruderfer, Eli A. Stahl & Pamela Sklar

  102. Departments of Psychiatry and Human Genetics, University of Chicago, Chicago, IL, USA

    Elliot S. Gershon

  103. Department of Psychiatry, University of Munich, Munich, Germany

    Ina Giegling,  Dan Rujescu & Dan Rujescu

  104. Departments of Psychiatry and Human and Molecular Genetics, INSERM, Institut de Myologie, Hôpital de la Pitiè-Salpêtrière, Paris, France

    Stephanie Godard

  105. Mental Health Research Centre, Russian Academy of Medical Sciences, Moscow, Russia

    Vera Golimbet

  106. Neuroscience Therapeutic Area, Janssen Research and Development, Raritan, NJ, USA

    Srihari Gopal, Dai Wang & Qingqin S. Li

  107. Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia

    Jacob Gratten, S. Hong Lee, Naomi R. Wray, Peter M. Visscher & Bryan J. Mowry

  108. Department of Psychiatry, Academic Medical Centre University of Amsterdam, Amsterdam, The Netherlands

    Lieuwe de Haan & Carin J. Meijer

  109. Illumina, La Jolla, CA, USA

    Mark Hansen

  110. Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Copenhagen, Denmark

    Thomas Hansen, Line Olsen, Henrik B. Rasmussen & Thomas Werge

  111. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Vahram Haroutunian, Joseph D. Buxbaum & Pamela Sklar

  112. J. J. Peters VA Medical Center, Bronx, New York, NY, USA

    Vahram Haroutunian

  113. Priority Research Centre for Health Behaviour, University of Newcastle, Newcastle, New South Wales, Australia

    Frans A. Henskens

  114. School of Electrical Engineering and Computer Science, University of Newcastle, Newcastle, New South Wales, Australia

    Frans A. Henskens

  115. Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland

    Stefan Herms, Per Hoffmann & Sven Cichon

  116. Department of Genetics, Harvard Medical School, Boston, MA, USA

    Joel N. Hirschhorn, Tõnu Esko & Steven A. McCarroll

  117. Section of Neonatal Screening and Hormones, Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Copenhagen, Denmark

    Mads V. Hollegaard & David M. Hougaard

  118. Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Japan

    Masashi Ikeda & Nakao Iwata

  119. Regional Centre for Clinical Research in Psychosis, Department of Psychiatry, Stavanger University Hospital, Stavanger, Norway

    Inge Joa

  120. Rheumatology Research Group, Vall d’Hebron Research Institute, Barcelona, Spain

    Antonio Julià & Sara Marsal

  121. Centre for Medical Research, The University of Western Australia, Perth, Western Australia, Australia

    Luba Kalaydjieva & Luba Kalaydjieva

  122. Department of Medical Genetics, Medical University, Sofia, Bulgaria

    Sena Karachanak-Yankova & Draga Toncheva

  123. Department of Psychology, University of Colorado Boulder, Boulder, CO, USA

    Matthew C. Keller

  124. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    James L. Kennedy, Clement C. Zai & Jo Knight

  125. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    James L. Kennedy, Clement C. Zai & Jo Knight

  126. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    James L. Kennedy & Jo Knight

  127. Institute of Molecular Genetics, Russian Academy of Sciences, Moscow, Russia

    Andrey Khrunin, Svetlana Limborska & Petr Slominsky

  128. Latvian Biomedical Research and Study Centre, Riga, Latvia

    Janis Klovins & Liene Nikitina-Zake

  129. Department of Psychiatry and Zilkha Neurogenetics Institute, Keck School of Medicine at University of Southern California, Los Angeles, CA, USA

    James A. Knowles, Michele T. Pato & Carlos N. Pato

  130. Faculty of Medicine, Vilnius University, Vilnius, Lithuania

    Vaidutis Kucinskas & Zita Ausrele Kucinskiene

  131. Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic

    Hana Kuzelova-Ptackova & Milan Macek Jr

  132. Department of Child and Adolescent Psychiatry, Pierre and Marie Curie Faculty of Medicine, Paris, France

    Claudine Laurent

  133. Duke-NUS Graduate Medical School, Singapore, Singapore

    Jimmy Lee Chee Keong

  134. Department of Psychiatry, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    Bernard Lerer

  135. Centre for Genomic Sciences, The University of Hong Kong, Hong Kong, China

    Miaoxin Li & Pak C. Sham

  136. Mental Health Centre and Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, China

    Tao Li & Qiang Wang

  137. Department of Biostatistics, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA

    Kung-Yee Liang

  138. Department of Psychiatry, Columbia University, New York, NY, USA

    Jeffrey Lieberman & T. Scott Stroup

  139. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Szczecin, Poland

    Jan Lubinski

  140. Department of Mental Health and Substance Abuse Services, National Institute for Health and Welfare, Helsinki, Finland

    Jouko Lönnqvist & Jaana Suvisaari

  141. Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    Brion S. Maher

  142. Department of Psychiatry, University of Bonn, Bonn, Germany

    Wolfgang Maier

  143. Centre National de la Recherche Scientifique, Laboratoire de Génétique Moléculaire de la Neurotransmission et des Processus Neurodégénératifs, Hôpital de la Pitié Salpêtrière, Paris, France

    Jacques Mallet

  144. Department of Genomics Mathematics, University of Bonn, Bonn, Germany

    Manuel Mattheisen

  145. Research Unit, Sørlandet Hospital, Kristiansand, Norway

    Morten Mattingsdal

  146. Department of Psychiatry, National University of Ireland Galway, Galway, Ireland

    Colm McDonald

  147. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK

    Andrew M. McIntosh

  148. Division of Psychiatry, University of Edinburgh, Edinburgh, UK

    Andrew M. McIntosh, Douglas H. R. Blackwood, Jeremy Hall, Stephen Lawrie & Andrew M. McIntosh

  149. Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

    Ingrid Melle & Ole A. Andreassen

  150. Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Boston, MA, USA

    Raquelle I. Mesholam-Gately & Larry J. Seidman

  151. Estonian Genome Center, University of Tartu, Tartu, Estonia

    Andres Metspalu, Lili Milani, Mari Nelis & Tõnu Esko

  152. School of Psychology, University of Newcastle, Newcastle, New South Wales, Australia

    Patricia T. Michie

  153. First Psychiatric Clinic, Medical University, Sofia, Bulgaria

    Vihra Milanova

  154. Department P, Aarhus University Hospital, Risskov, Denmark

    Ole Mors & Anders D. Børglum

  155. Department of Psychiatry, Royal College of Surgeons in Ireland, Dublin, Ireland

    Kieran C. Murphy

  156. King’s College London, London, UK

    Robin M. Murray, John Powell & Robin M. Murray

  157. South Limburg Mental Health Research and Teaching Network, EURON, Maastricht University Medical Centre, Maastricht, The Netherlands

    Inez Myin-Germeys, Jim Van Os & Jim Van Os

  158. Institute of Translational Medicine, University of Liverpool, Liverpool, UK

    Bertram Müller-Myhsok

  159. Max Planck Institute of Psychiatry, Munich, Germany

    Bertram Müller-Myhsok

  160. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    Bertram Müller-Myhsok

  161. Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany

    Igor Nenadic

  162. Department of Psychiatry, Queensland Brain Institute and Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia

    Deborah A. Nertney

  163. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Gerald Nestadt & Ann E. Pulver

  164. Department of Psychiatry, Trinity College Dublin, Dublin, Ireland

    Kristin K. Nicodemus

  165. Eli Lilly, Lilly Corporate Center, Indianapolis, IN, USA

    Laura Nisenbaum

  166. Department of Clinical Sciences, Psychiatry, Umeå University, Umeå, Sweden

    Annelie Nordin & Rolf Adolfsson

  167. DETECT Early Intervention Service for Psychosis, Blackrock, Ireland

    Eadbhard O’Callaghan

  168. Centre for Public Health, Institute of Clinical Sciences, Queen’s University Belfast, Belfast, UK

    F. Anthony O’Neill

  169. Lawrence Berkeley National Laboratory, University of California at Berkeley, Berkeley, CA, USA

    Sang-Yun Oh

  170. Institute of Psychiatry, King’s College London, London, UK

    Jim Van Os, Maria J. Arranz, Elvira Bramon, Conrad Iyegbe, Cathryn M. Lewis, Kuang Lin, Jim Van Os, John Powell & Muriel Walshe

  171. Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health, Melbourne, Victoria, Australia

    Christos Pantelis

  172. Department of Psychiatry, University of Helsinki, Helsinki, Finland

    Tiina Paunio

  173. Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland

    Tiina Paunio & Olli Pietiläinen

  174. Medical Faculty, University of Belgrade, Belgrade, Serbia

    Milica Pejovic-Milovancevic

  175. Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA

    Diana O. Perkins & Patrick F. Sullivan

  176. Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland

    Olli Pietiläinen & Aarno Palotie

  177. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA

    Alkes Price

  178. Department of Psychiatry, University of Oxford, Oxford, UK

    Digby Quested

  179. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    Mark A. Reimers & Aaron R. Wolen

  180. Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Panos Roussos & Pamela Sklar

  181. PharmaTherapeutics Clinical Research, Pfizer Worldwide Research and Development, Cambridge, MA, USA

    Christian R. Schubert & Jens R. Wendland

  182. Department of Psychiatry and Psychotherapy, University of Gottingen, Göttingen, Germany

    Thomas G. Schulze

  183. Psychiatry and Psychotherapy Clinic, University of Erlangen, Erlangen, Germany

    Sibylle G. Schwab

  184. Hunter New England Health Service, Newcastle, New South Wales, Australia

    Rodney J. Scott

  185. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA

    Jianxin Shi

  186. University of Iceland, Landspitali, National University Hospital, Reykjavik, Iceland

    Engilbert Sigurdsson

  187. Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia

    Teimuraz Silagadze

  188. Research and Development, Bronx Veterans Affairs Medical Center, New York, NY, USA

    Jeremy M. Silverman

  189. Wellcome Trust Centre for Human Genetics, Oxford, UK

    Chris C. A. Spencer

  190. deCODE Genetics, Reykjavik, Iceland

    Hreinn Stefansson, Stacy Steinberg & Kari Stefansson

  191. Department of Clinical Neurology, Medical University of Vienna, Vienna, Austria

    Elisabeth Stogmann & Fritz Zimprich

  192. Lieber Institute for Brain Development, Baltimore, MD, USA

    Richard E. Straub, Daniel R. Weinberger, Peter Donnelly, Anna Rautanen, Chris C. A. Spencer, Gavin Band, Céline Bellenguez, Peter Donnelly, Colin Freeman, Eleni Giannoulatou, Garrett Hellenthal, Richard Pearson, Matti Pirinen, Amy Strange, Zhan Su, Damjan Vukcevic & Chris C. A. Spencer

  193. Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands

    Eric Strengman

  194. Berkshire Healthcare NHS Foundation Trust, Bracknell, UK

    Srinivas Thirumalai

  195. Section of Psychiatry, University of Verona, Verona, Italy

    Sarah Tosato

  196. Department of Psychiatry, University of Oulu, Oulu, Finland

    Juha Veijola

  197. University Hospital of Oulu, Oulu, Finland

    Juha Veijola

  198. Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland

    John Waddington

  199. Health Research Board, Dublin, Ireland

    Dermot Walsh

  200. School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Western Australia, Australia

    Dieter B. Wildenauer & Assen V. Jablensky

  201. Computational Sciences CoE, Pfizer Worldwide Research and Development, Cambridge, MA, USA

    Hualin Simon Xi

  202. Human Genetics, Genome Institute of Singapore, A*STAR, Singapore, Singapore

    Xuebin Zheng & Jianjun Liu

  203. University College London, London, UK

    Elvira Bramon

  204. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Joseph D. Buxbaum

  205. Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany

    Sven Cichon & Elvira Bramon

  206. Department of Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel

    Ariel Darvasi

  207. Neuroscience Discovery and Translational Area, Pharma Research and Early Development, F. Hoffman-La Roche, Basel, Switzerland

    Enrico Domenici

  208. The Perkins Institute for Medical Research, The University of Western Australia, Perth, Western Australia, Australia

    Assen V. Jablensky

  209. Centre for Clinical Research in Neuropsychiatry, School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, Western Australia, Australia

    Assen V. Jablensky

  210. Virginia Institute for Psychiatric and Behavioral Genetics, Departments of Psychiatry and Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA

    Kenneth S. Kendler & Brien P. Riley

  211. The Feinstein Institute for Medical Research, Manhasset, NY, USA

    Todd Lencz & Anil K. Malhotra

  212. The Hofstra NS-LIJ School of Medicine, Hempstead, NY, USA

    Todd Lencz & Anil K. Malhotra

  213. The Zucker Hillside Hospital, Glen Oaks, NY, USA

    Todd Lencz & Anil K. Malhotra

  214. Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore

    Jianjun Liu

  215. Queensland Centre for Mental Health Research, University of Queensland, Brisbane, Queensland, Australia

    Bryan J. Mowry

  216. Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

    Tracey L. Petryshen

  217. Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam, The Netherlands

    Danielle Posthuma

  218. Department of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU University Medical Center Amsterdam, Amsterdam, The Netherlands

    Danielle Posthuma

  219. Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands

    Danielle Posthuma

  220. University of Aberdeen, Institute of Medical Sciences, Aberdeen, UK

    David St Clair

  221. Departments of Psychiatry, Neurology, Neuroscience and Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Daniel R. Weinberger

  222. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Thomas Werge

  223. Fundació de Docència i Recerca Mútua de Terrassa, Universitat de Barcelona, Barcelona, Spain

    Maria J. Arranz

  224. Child and Adolescent Psychiatry, University of Technology Dresden, Dresden, Germany

    Stephan Bender

  225. Section for Experimental Psychopathology, General Psychiatry, Heidelberg, Germany

    Stephan Bender & Matthias Weisbrod

  226. Institute of Cognitive Neuroscience, University College London, London, UK

    Elvira Bramon

  227. Mental Health Sciences Unit, University College London, London, UK

    Elvira Bramon

  228. Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain

    Benedicto Crespo-Facorro & Ignacio Mata

  229. University Hospital Marqués de Valdecilla, Instituto de Formación e Investigación Marqués de Valdecilla, University of Cantabria, Santander, Spain

    Benedicto Crespo-Facorro & Ignacio Mata

  230. Centre for Clinical Research in Neuropsychiatry, The University of Western Australia, Perth, Western Australia, Australia

    Assen V. Jablensky

  231. Western Australian Institute for Medical Research, The University of Western Australia, Perth, Western Australia, Australia

    Luba Kalaydjieva

  232. Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    Don H. Linszen

  233. Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

    Durk Wiersma

  234. Department of Statistics, University of Oxford, Oxford, UK

    Peter Donnelly & Peter Donnelly

  235. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK

    Ines Barroso, Panos Deloukas, Cordelia Langford, Ines Barroso, Hannah Blackburn, Suzannah J. Bumpstead, Panos Deloukas, Serge Dronov, Sarah Edkins, Matthew Gillman, Emma Gray, Rhian Gwilliam, Naomi Hammond, Sarah E. Hunt, Alagurevathi Jayakumar, Jennifer Liddle, Owen T. McCann, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Avazeh Tashakkori-Ghanbaria, Matthew Waller, Paul Weston, Pamela Whittaker & Sara Widaa

  236. Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Cambridge, UK

    Jenefer M. Blackwell & Jenefer M. Blackwell

  237. Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Subiaco, Western Australia, Australia

    Jenefer M. Blackwell & Jenefer M. Blackwell

  238. Diamantina Institute of Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia

    Matthew A. Brown & Matthew A. Brown

  239. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK

    Juan P. Casas

  240. Department of Epidemiology and Public Health, University College London, London, UK

    Juan P. Casas

  241. Molecular and Physiological Sciences, The Wellcome Trust, London, UK

    Audrey Duncanson

  242. Peninsula School of Medicine and Dentistry, Plymouth University, Plymouth, UK

    Janusz Jankowski

  243. Clinical Neurosciences, St George’s University of London, London, UK

    Hugh S. Markus

  244. Department of Medical and Molecular Genetics, School of Medicine, Guy’s Hospital, King’s College London, London, UK

    Christopher G. Mathew, Richard C. Trembath & Christopher G. Mathew

  245. Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK

    Colin N. A. Palmer

  246. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

    Stephen J. Sawcer

  247. Institute of Ophthalmology, University College London, London, UK

    Ananth C. Viswanathan

  248. National Institute for Health Research, Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, London, UK

    Ananth C. Viswanathan

  249. Department of Molecular Neuroscience, Institute of Neurology, London, UK

    Nicholas W. Wood

  250. Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford, UK

    Mark I. McCarthy

Authors
  1. Nolan Kamitaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aswin Sekar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Robert E. Handsaker
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Heather de Rivera
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Katherine Tooley
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. David L. Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kimberly E. Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christopher W. Whelan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Philip Tombleson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Loes M. Olde Loohuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Michael Boehnke
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Robert P. Kimberly
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Kenneth M. Kaufman
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. John B. Harley
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Carl D. Langefeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Christine E. Seidman
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Michele T. Pato
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Carlos N. Pato
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Roel A. Ophoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Robert R. Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Lindsey A. Criswell
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Timothy J. Vyse
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Steven A. McCarroll
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

Schizophrenia Working Group of the Psychiatric Genomics Consortium

  • Stephan Ripke
  • , Benjamin M. Neale
  • , Aiden Corvin
  • , James T. R. Walters
  • , Kai-How Farh
  • , Peter A. Holmans
  • , Phil Lee
  • , Brendan Bulik-Sullivan
  • , David A. Collier
  • , Hailiang Huang
  • , Tune H. Pers
  • , Ingrid Agartz
  • , Esben Agerbo
  • , Margot Albus
  • , Madeline Alexander
  • , Farooq Amin
  • , Silviu A. Bacanu
  • , Martin Begemann
  • , Richard A. Belliveau Jr
  • , Judit Bene
  • , Sarah E. Bergen
  • , Elizabeth Bevilacqua
  • , Tim B. Bigdeli
  • , Donald W. Black
  • , Richard Bruggeman
  • , Nancy G. Buccola
  • , Randy L. Buckner
  • , William Byerley
  • , Wiepke Cahn
  • , Guiqing Cai
  • , Murray J. Cairns
  • , Dominique Campion
  • , Rita M. Cantor
  • , Vaughan J. Carr
  • , Noa Carrera
  • , Stanley V. Catts
  • , Kimberly D. Chambert
  • , Raymond C. K. Chan
  • , Ronald Y. L. Chen
  • , Eric Y. H. Chen
  • , Wei Cheng
  • , Eric F. C. Cheung
  • , Siow Ann Chong
  • , C. Robert Cloninger
  • , David Cohen
  • , Nadine Cohen
  • , Paul Cormican
  • , Nick Craddock
  • , Benedicto Crespo-Facorro
  • , James J. Crowley
  • , David Curtis
  • , Michael Davidson
  • , Kenneth L. Davis
  • , Franziska Degenhardt
  • , Jurgen Del Favero
  • , Lynn E. DeLisi
  • , Ditte Demontis
  • , Dimitris Dikeos
  • , Timothy Dinan
  • , Srdjan Djurovic
  • , Gary Donohoe
  • , Elodie Drapeau
  • , Jubao Duan
  • , Frank Dudbridge
  • , Naser Durmishi
  • , Peter Eichhammer
  • , Johan Eriksson
  • , Valentina Escott-Price
  • , Laurent Essioux
  • , Ayman H. Fanous
  • , Martilias S. Farrell
  • , Josef Frank
  • , Lude Franke
  • , Robert Freedman
  • , Nelson B. Freimer
  • , Marion Friedl
  • , Joseph I. Friedman
  • , Menachem Fromer
  • , Giulio Genovese
  • , Lyudmila Georgieva
  • , Elliot S. Gershon
  • , Ina Giegling
  • , Paola Giusti-Rodríguez
  • , Stephanie Godard
  • , Jacqueline I. Goldstein
  • , Vera Golimbet
  • , Srihari Gopal
  • , Jacob Gratten
  • , Lieuwe de Haan
  • , Marina Mitjans
  • , Marian L. Hamshere
  • , Mark Hansen
  • , Thomas Hansen
  • , Vahram Haroutunian
  • , Annette M. Hartmann
  • , Frans A. Henskens
  • , Stefan Herms
  • , Joel N. Hirschhorn
  • , Per Hoffmann
  • , Andrea Hofman
  • , Mads V. Hollegaard
  • , David M. Hougaard
  • , Masashi Ikeda
  • , Inge Joa
  • , Antonio Julià
  • , René S. Kahn
  • , Luba Kalaydjieva
  • , Sena Karachanak-Yankova
  • , Juha Karjalainen
  • , David Kavanagh
  • , Matthew C. Keller
  • , Brian J. Kelly
  • , James L. Kennedy
  • , Andrey Khrunin
  • , Yunjung Kim
  • , Janis Klovins
  • , James A. Knowles
  • , Bettina Konte
  • , Vaidutis Kucinskas
  • , Zita Ausrele Kucinskiene
  • , Hana Kuzelova-Ptackova
  • , Anna K. Kähler
  • , Claudine Laurent
  • , Jimmy Lee Chee Keong
  • , S. Hong Lee
  • , Sophie E. Legge
  • , Bernard Lerer
  • , Miaoxin Li
  • , Tao Li
  • , Kung-Yee Liang
  • , Jeffrey Lieberman
  • , Svetlana Limborska
  • , Carmel M. Loughland
  • ,  Jan Lubinski
  • , Jouko Lönnqvist
  • , Milan Macek Jr
  • , Patrik K. E. Magnusson
  • , Brion S. Maher
  • , Wolfgang Maier
  • , Jacques Mallet
  • , Sara Marsal
  • , Manuel Mattheisen
  • , Morten Mattingsdal
  • , Robert W. McCarley
  • , Colm McDonald
  • , Andrew M. McIntosh
  • , Sandra Meier
  • , Carin J. Meijer
  • , Bela Melegh
  • , Ingrid Melle
  • , Raquelle I. Mesholam-Gately
  • , Andres Metspalu
  • , Patricia T. Michie
  • , Lili Milani
  • , Vihra Milanova
  • , Younes Mokrab
  • , Derek W. Morris
  • , Ole Mors
  • , Kieran C. Murphy
  • , Robin M. Murray
  • , Inez Myin-Germeys
  • , Bertram Müller-Myhsok
  • , Mari Nelis
  • , Igor Nenadic
  • , Deborah A. Nertney
  • , Gerald Nestadt
  • , Kristin K. Nicodemus
  • , Liene Nikitina-Zake
  • , Laura Nisenbaum
  • , Annelie Nordin
  • , Eadbhard O’Callaghan
  • , Colm O’Dushlaine
  • , F. Anthony O’Neill
  • , Sang-Yun Oh
  • , Ann Olincy
  • , Line Olsen
  • , Jim Van Os
  • , Psychosis Endophenotypes International Consortium
  • , Christos Pantelis
  • , George N. Papadimitriou
  • , Agnes A. Steixner
  • , Elena Parkhomenko
  • , Michele T. Pato
  • , Tiina Paunio
  • , Milica Pejovic-Milovancevic
  • , Diana O. Perkins
  • , Olli Pietiläinen
  • , Jonathan Pimm
  • , Andrew J. Pocklington
  • , John Powell
  • , Alkes Price
  • , Ann E. Pulver
  • , Shaun M. Purcell
  • , Digby Quested
  • , Henrik B. Rasmussen
  • , Abraham Reichenberg
  • , Mark A. Reimers
  • , Alexander L. Richards
  • , Joshua L. Roffman
  • , Panos Roussos
  • , Douglas M. Ruderfer
  • , Veikko Salomaa
  • , Alan R. Sanders
  • , Ulrich Schall
  • , Christian R. Schubert
  • , Thomas G. Schulze
  • , Sibylle G. Schwab
  • , Edward M. Scolnick
  • , Rodney J. Scott
  • , Larry J. Seidman
  • , Jianxin Shi
  • , Engilbert Sigurdsson
  • , Teimuraz Silagadze
  • , Jeremy M. Silverman
  • , Kang Sim
  • , Petr Slominsky
  • , Jordan W. Smoller
  • , Hon-Cheong So
  • , Chris C. A. Spencer
  • , Eli A. Stahl
  • , Hreinn Stefansson
  • , Stacy Steinberg
  • , Elisabeth Stogmann
  • , Richard E. Straub
  • , Eric Strengman
  • , Jana Strohmaier
  • , T. Scott Stroup
  • , Mythily Subramaniam
  • , Jaana Suvisaari
  • , Dragan M. Svrakic
  • , Jin P. Szatkiewicz
  • , Erik Söderman
  • , Srinivas Thirumalai
  • , Draga Toncheva
  • , Paul A. Tooney
  • , Sarah Tosato
  • , Juha Veijola
  • , John Waddington
  • , Dermot Walsh
  • , Dai Wang
  • , Qiang Wang
  • , Bradley T. Webb
  • , Mark Weiser
  • , Dieter B. Wildenauer
  • , Nigel M. Williams
  • , Stephanie Williams
  • , Stephanie H. Witt
  • , Aaron R. Wolen
  • , Emily H. M. Wong
  • , Brandon K. Wormley
  • , Jing Qin Wu
  • , Hualin Simon Xi
  • , Clement C. Zai
  • , Xuebin Zheng
  • , Fritz Zimprich
  • , Naomi R. Wray
  • , Kari Stefansson
  • , Peter M. Visscher
  • , Wellcome Trust Case–Control Consortium 2
  • , Rolf Adolfsson
  • , Ole A. Andreassen
  • , Douglas H. R. Blackwood
  • , Elvira Bramon
  • , Joseph D. Buxbaum
  • , Anders D. Børglum
  • , Sven Cichon
  • , Ariel Darvasi
  • , Enrico Domenici
  • , Hannelore Ehrenreich
  • , Tõnu Esko
  • , Pablo V. Gejman
  • , Michael Gill
  • , Hugh Gurling
  • , Christina M. Hultman
  • , Nakao Iwata
  • , Assen V. Jablensky
  • , Erik G. Jönsson
  • , Kenneth S. Kendler
  • , George Kirov
  • , Jo Knight
  • , Todd Lencz
  • , Douglas F. Levinson
  • , Qingqin S. Li
  • , Jianjun Liu
  • , Anil K. Malhotra
  • , Steven A. McCarroll
  • , Andrew McQuillin
  • , Jennifer L. Moran
  • , Preben B. Mortensen
  • , Bryan J. Mowry
  • , Markus M. Nöthen
  • , Roel A. Ophoff
  • , Michael J. Owen
  • , Aarno Palotie
  • , Carlos N. Pato
  • , Tracey L. Petryshen
  • , Danielle Posthuma
  • , Marcella Rietschel
  • , Brien P. Riley
  • ,  Dan Rujescu
  • , Pak C. Sham
  • , Pamela Sklar
  • , David St Clair
  • , Daniel R. Weinberger
  • , Jens R. Wendland
  • , Thomas Werge
  • , Mark J. Daly
  • , Patrick F. Sullivan
  • , Michael C. O’Donovan

  • Psychosis Endophenotype International Consortium

    • Maria J. Arranz
    • , Steven Bakker
    • , Stephan Bender
    • , Elvira Bramon
    • , David A. Collier
    • , Benedicto Crespo-Facorro
    • , Jeremy Hall
    • , Conrad Iyegbe
    • , Assen V. Jablensky
    • , René S. Kahn
    • , Luba Kalaydjieva
    • , Stephen Lawrie
    • , Cathryn M. Lewis
    • , Kuang Lin
    • , Don H. Linszen
    • , Ignacio Mata
    • , Andrew M. McIntosh
    • , Robin M. Murray
    • , Roel A. Ophoff
    • , Jim Van Os
    • , John Powell
    • , Dan Rujescu
    • , Muriel Walshe
    • , Matthias Weisbrod
    •  & Durk Wiersma

  • Wellcome Trust Case–Control Consortium 2

    • Peter Donnelly
    • , Ines Barroso
    • , Jenefer M. Blackwell
    • , Elvira Bramon
    • , Matthew A. Brown
    • , Juan P. Casas
    • , Aiden Corvin
    • , Panos Deloukas
    • , Audrey Duncanson
    • , Janusz Jankowski
    • , Hugh S. Markus
    • , Christopher G. Mathew
    • , Colin N. A. Palmer
    • , Robert Plomin
    • , Anna Rautanen
    • , Stephen J. Sawcer
    • , Richard C. Trembath
    • , Ananth C. Viswanathan
    • , Nicholas W. Wood
    • , Chris C. A. Spencer
    • , Gavin Band
    • , Céline Bellenguez
    • , Peter Donnelly
    • , Colin Freeman
    • , Eleni Giannoulatou
    • , Garrett Hellenthal
    • , Richard Pearson
    • , Matti Pirinen
    • , Amy Strange
    • , Zhan Su
    • , Damjan Vukcevic
    • , Cordelia Langford
    • , Ines Barroso
    • , Hannah Blackburn
    • , Suzannah J. Bumpstead
    • , Panos Deloukas
    • , Serge Dronov
    • , Sarah Edkins
    • , Matthew Gillman
    • , Emma Gray
    • , Rhian Gwilliam
    • , Naomi Hammond
    • , Sarah E. Hunt
    • , Alagurevathi Jayakumar
    • , Jennifer Liddle
    • , Owen T. McCann
    • , Simon C. Potter
    • , Radhi Ravindrarajah
    • , Michelle Ricketts
    • , Avazeh Tashakkori-Ghanbaria
    • , Matthew Waller
    • , Paul Weston
    • , Pamela Whittaker
    • , Sara Widaa
    • , Christopher G. Mathew
    • , Jenefer M. Blackwell
    • , Matthew A. Brown
    • , Aiden Corvin
    • , Mark I. McCarthy
    •  & Chris C. A. Spencer

Contributions

N.K., A.S., T.J.V. and S.A.M. conceived the genetic studies. M.T.P., C.N.P. and M.B. collected and contributed WGS data for the Genomic Psychiatry Cohort. R.E.H. and C.W.W. genotyped C4 structural variation in the Genomic Psychiatry Cohort and optimized variant selection for use as a reference panel in the imputation of C4 variation into lupus and schizophrenia cohorts (Extended Data Fig. 1). T.J.V., R.R.G., L.A.C., C.D.L., R.P.K., J.B.H., K.M.K., D.L.M. and P.T. contributed genotype data and imputation of non-C4 variation for analysis of SLE cohorts. K.E.T. and L.A.C. contributed genotype and phenotype data along with imputation of non-C4 variation for analysis of the Sjögren’s syndrome cohort. Investigators in the Schizophrenia Working Group of the Psychiatric Genomics Consortium collected and phenotyped cohorts and contributed genotype data for analysis of schizophrenia cohorts. N.K. did the imputation and association analysis (Figs. 1, 2, 3a, b, Extended Data Figs. 2–6). T.J.V., R.R.G. and D.L.M. provided valuable advice on the analysis and interpretation of SLE-association results. R.A.O. and L.M.O.L. collected and provided CSF samples composing the group from Utrecht, Netherlands. C.E.S. collected and provided CSF samples composing the Brigham & Women’s Hospital group. H.d.R and K.T. performed the C4 and C3 immunoassay experiments on CSF samples (Fig. 3c, d, Extended Data Fig. 7a). N.K. did the analysis of plasma C4 and C3 concentrations (Extended Data Fig. 7b–f). S.A.M and N.K. wrote the manuscript with contributions from all authors. Management Committee of Wellcome Trust Case–Control Consortium 2: P.D., I.B., J.M.B., E.B., M.A.B., J.P.C., A.C., P.D., A.D., J.J., H.S.M., C.G.M., C.N.A.P., R.P., A.R., S.J.S., R.C.T., A.C.V. and N.W.W; Data and Analysis Group of Wellcome Trust Case–Control Consortium 2: C.C.A.S., G.B., C.B., P.D., C.F., E.G., G.H., R.P., M.P., A.S., Z.S., D.V.; DNA, Genotyping, Data QC, and Informatics of Wellcome Trust Case–Control Consortium 2: C.L., I.B., H.B., S.J.B., P.D., S.D., S.E., M.G., E.G., R.G., N.H., S.E.H., A.J., J.L., O.T.M., S.C.P., R.R., M.R., A.T.-G., M.W., P.W., P.W., S.W.; Publications Committee of Wellcome Trust Case–Control Consortium 2: C.G.M., J.M.B., M.A.B., A.C., M.I..M. and C.C.A.S.

Corresponding authors

Correspondence to Nolan Kamitaki, Timothy J. Vyse or Steven A. McCarroll.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature thanks John Armour and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended Data Fig. 1 A panel of 2,530 reference haplotypes (created from WGS data) containing C4 alleles and SNPs across the MHC genomic region enables imputation of C4 alleles into SNP data.

a, Distributions (across 1,265 individuals) of total C4 gene copy number (C4A + C4B), as measured from read depth of coverage across the C4 locus, in WGS data. b, The relative numbers of reads that overlap sequences specific to C4A or C4B (together with the total C4 gene copy number as in a) are used to infer the underlying copy numbers of the C4A and C4B genes. For example, in an individual with four C4 genes, the presence of equal numbers of reads specific to C4A or C4B suggests the presence of two copies each of C4A and C4B. Precise statistical approaches (including inference of probabilistic dosages) and further approaches for phasing C4 allelic states with nearby SNPs to create reference haplotypes, are described in Methods. c, The SNP haplotypes flanking each C4 allele are shown as rows (SNPs as columns), with white and black representing the major and minor allele of each SNP. Grey lines at the bottom indicate the physical location of each SNP along chromosome 6. The differences among the haplotypes are most pronounced closest to C4 (towards the centre of the plot), as historical recombination events in the flanking megabases will have caused the haplotypes to be less consistently distinct at greater genomic distances from C4. The patterns indicate that many combinations of C4A and C4B gene copy numbers have arisen recurrently on more than one SNP haplotype, a relationship that can be used in association analyses (Fig. 1b).

Extended Data Fig. 2 Aggregation of joint C4A and C4B genotype probabilities per individual across imputed C4 structural alleles for estimation of SLE risk for each combination.

a, An individual’s joint C4A and C4B gene copy number can be calculated by summing the C4A and C4B gene contents for each possible pair of two inherited alleles. Many pairings of possible inherited alleles result in the same joint C4A and C4B gene copy number. b, Each individual’s C4A and C4B gene copy number was imputed from their SNP data, using the reference haplotypes summarized in Extended Data Fig. 1c. For more than 95% of individuals (exemplified by samples 1–6 in the figure), this inference can be made with >90% certainty or confidence (the areas of the circles represent the posterior probability distribution over possible C4A/C4B gene copy numbers). For the remaining individuals (exemplified by samples 7–9 in the figure), greater statistical uncertainty persists about C4 genotype. To account for this uncertainty, in downstream association analysis, all C4 genotype assignments are handled as probabilistic gene dosages—analogous to the genotype dosages that are routinely used in large-scale genetic association studies that use imputation. c, Odds ratios and 95% confidence intervals underlying each of the C4-genotype risk estimates in Fig. 1a presented as a series of panels for each observed copy number of C4B, with increasing copy number of C4A for that C4B dosage (x-axis). Data are from analysis of 6,748 SLE cases and 11,516 controls of European ancestry.

Extended Data Fig. 3 Conditional association analyses for genetic markers across the extended MHC genomic region within the European-ancestry SLE and Sjögren’s syndrome cohorts.

a, Association of SLE with genetic markers (SNPs and imputed HLA alleles) across the extended MHC locus within the European-ancestry SLE cohort (6,748 cases and 11,516 controls). Orange diamond: an initial estimate of C4-related genetic risk, calculated as a weighted sum of the number of C4A and C4B gene copies: (2.3)C4A+C4B, with the weights derived from the relative coefficients estimated from logistic regression of SLE risk versus C4A and C4B gene dosages. This risk score is imputed with an accuracy (r2) of 0.77. Points representing all other genetic variants in the MHC locus are shaded orange according to their level of LD-based correlation to this C4-derived risk score. b, As in a, but for a European-ancestry Sjögren’s syndrome (SjS) cohort (673 cases and 1,153 controls). The orange diamond here also represents (2.3)C4A + C4B, with this weighting derived from the relative coefficients estimated from logistic regression of Sjögren’s syndrome risk versus C4A and C4B gene dosages. c, Association of SLE with genetic markers (SNPs and imputed HLA alleles) across the extended MHC locus within the European-ancestry SLE cohort controlling for C4 composite risk (weighted sum of risk associated with various combinations of C4A and C4B). Variants are shaded in purple by their LD with rs2105898, an independent association identified from trans-ancestral analyses. d, As in c, but in association with a European-ancestry Sjögren’s syndrome cohort. Here a simpler linear model of risk contributed by C4A and C4B was used instead of a weighted sum across all possible combinations.

Extended Data Fig. 4 Using C4 gene variation to understand the appearance of trans-ancestral disparity in MHC association signals, and to fine-map an additional genetic effect.

Association signals (for SLE and Sjögren’s syndrome) for variants in a multi-megabase region of human chromosome 6 containing the MHC region including the HLA and C4 genes. a, Relationship between SLE association (−log10(p), y-axis) and LD to the weighted C4 risk score (x axis) for genetic markers and imputed HLA alleles across the extended MHC locus. In this European-ancestry cohort, it is unclear (from this analysis alone) whether the association with the markers in the predominant ray of points (at an angle of ~45° from the x axis) is driven by variation at C4 or by the long haplotype containing DRB1*03:01 (green), DQA1*05:01 (blue), B*08:01 (red) and many other SNPs (black). In addition, at least one independent association signal (a ray of points at a higher angle in the plot, with strong association signals and only weak linkage disequilibirum-based correlation to C4 and DRB1*0301) with some LD to DRB1*15:01 (maroon) is also present. b, Analysis as in a, but for associations to Sjögren’s syndrome in a cohort of European ancestry. As in SLE, it is initially unclear whether the genetic association signal is driven by variation at C4 or by linked HLA alleles, DRB1*03:01 (green), DQA1*05:01 (blue), and B*08:01 (red). There is also an independent association signal with LD to DRB1*15:01 (maroon). c, Analysis as in a, but of an African American SLE case–control cohort (in which LD in the MHC region is more limited). Many MHC-region SNPs associate with SLE in proportion to their LD with the weighted C4 risk score inferred from the earlier analysis of the European-ancestry cohort; this C4-derived risk score itself associates with SLE at P = 4.3 × 10−19 in a logistic regression on 1,494 SLE cases and 5,908 controls. No similarly strong association is observed for DRB1*03:01, DQA1*05:01 or B*08:01, HLA alleles which are in strong LD with C4 risk on European-ancestry (but not African American) haplotypes. An independent association signal is also present in this cohort, more clearly in LD with the DRB1*15:03 allele (maroon). d, LD in the European-ancestry SLE cohort between the composite C4 risk term (weighted sum of risk associated with various combinations of C4A and C4B from Fig. 2a) and variants in the MHC region as r2 (y-axis). e, As in d, but for the African American SLE cohort. f, LD (to C4 composite risk) for the same variants in European-ancestry individuals (x axis) and African Americans (y axis). Note the abundance of variants that have greater LD with C4 risk among European-ancestry individuals than among African Americans. Also, several groups of variants have equivalent LD (to C4 risk) in European ancestry individuals but exhibit a range of LD to C4 risk among African Americans. g, Associations with SLE (−log10 P values) for the same variants in European ancestry (x axis) and African American (y axis) case–control cohorts. Orange shading represents the extent of LD with C4 risk in European ancestry individuals. Variants with strong European-specific association to SLE are generally in strong LD with C4 risk among European-ancestry individuals. h, Comparison of the inferred effect size from association of genetic markers with SLE (unconditioned log odds ratios) among European-ancestry (x axis) and African American (y axis) research participants. As also seen in g, variants with discordant associations to SLE (across populations) tend also to be in strong LD to C4 risk among European-ancestry individuals. i, As in g, but now controlling for the effect of C4 variation in analysis of the European-ancestry cohort (x axis). Note that controlling for C4 risk in European-ancestry individuals alone greatly aligns (relative to g) the patterns of association between European ancestry and African American cohorts. j, As in i, but now also controlling for the effect of C4 in associations of the African American cohort. Note that due to the lack of strong LD relationships between C4 and variants in the MHC region in African Americans (e), this further adjustment does not change results strongly (relative to i). The independent signal, rs2105898, and HLA alleles, DRB1*15:01 and DRB1*15:03, are also highlighted. LD with rs2105898 in European-ancestry individuals is indicated by purple shading. k, Comparison of the inferred effect sizes from association of genetic markers with SLE (log odds ratios) controlling for C4-derived risk among European-ancestry (x axis) and African American (y axis) research participants. Two SNPs (rs2105898 and rs9271513) that form a short haplotype common to both ancestry groups are among the strongest associations in both cohorts. (Their association to SLE in the European-ancestry cohort was initially much less remarkable than that of other SNPs that are in strong LD with C4.) LD with rs2105898 in European-ancestry individuals is indicated by purple shading. l, As in i, but with variants shaded by whether they exhibit greater LD to rs2105898 in Europeans (blue) or African Americans (red).

Extended Data Fig. 5 Relationship of rs2105898 alleles to a known ZNF143 binding motif in the XL9 region of the MHC class II locus.

a, Location of rs2105898 (yellow line at centre) within the XL9 region, with relevant tracks showing overlapping histone marks and transcription factor binding peaks (from ENCODE52), visualized with the UCSC genome browser53. b, ZNF143 consensus binding motif as a sequence logo, with the letters coloured if the base is present in more than 5% of observed instances. The alleles of rs2105898 are indicated by outlined box surrounding the base.

Extended Data Fig. 6 Relationships between sex bias of disease associations and LD to C4 risk for variants in the MHC region.

a, Relationship between male bias in SLE risk (difference between male and female log–odds ratios) and LD with C4 risk for common (minor allele frequency (MAF) > 0.1) genetic markers across the extended MHC region (6,748 cases and 11,516 controls). For each SNP, the allele for which sex risk bias is plotted is the allele that is positively correlated (via LD) with C4-derived risk score. b, Relationship between male bias in Sjögren’s syndrome risk (log-odds ratios) and LD with C4 risk for common (MAF > 0.1) genetic markers across the extended MHC region (673 cases and 1,153 controls). For each SNP, the allele for which sex risk bias is plotted is the allele that is positively correlated (via LD) with C4-derived risk score. c, Relationship of male bias in schizophrenia risk (log odds ratios) and LD to C4A expression for common (MAF >0.1) genetic markers across the extended MHC region (28,799 cases and 35,986 controls). For each SNP, the allele for which sex risk bias is plotted is the allele that is positively correlated (via LD) with imputed C4A expression, as previously described7.

Extended Data Fig. 7 Correlation of C4 protein measurements in CSF and blood plasma with imputed C4 gene copy number and relationship of plasma complement to sex and Sjögren’s syndrome status.

a, Measurements of C4 protein in CSF obtained by ELISA (n = 507 total) are presented as log10[concentration (ng ml−1)] (y axis) for each observed or imputed copy number of total C4 (x axis, here showing most likely copy number from imputation). Because C4 gene copy number affects C4 protein levels so strongly, we normalized C4 protein measurements to each donor’s C4 gene copy number in subsequent analyses (Fig. 3c). Bars indicate median values for each C4 copy number. b, Measurements of C4 protein in blood plasma obtained by immunoturbidimetric assays are presented as log10[concentration (mg dl−1)] (y axis) for each imputed most-likely copy number of C4 genes (x axis). Because C4 gene copy number affects C4 protein levels so strongly, we normalized C4 protein measurements by C4 gene copy number in subsequent analyses as in c. Due to the number of observations (n = 1,844 total), the plot is downsampled to 500 points; the median bars shown are for all individuals (before downsampling). c, Levels of C4 protein in blood plasma from 182 adult men and 1,662 adult women as a function of age. Concentrations are normalized to the number of C4 gene copies in an individual’s genome (a strong independent source of variance) and shown on a log10 scale as a LOESS curve. Shaded regions represent 95% confidence intervals derived during LOESS. d, Levels of C3 protein in blood plasma as a function of age from the same individuals in panel c. Concentrations are shown on a log10 scale as a LOESS curve. Shaded regions represent 95% confidence intervals derived during LOESS. e, C4 protein in blood plasma was measured in 670 individuals with Sjögren’s syndrome (red) and 1,151 individuals without Sjögren’s syndrome (black) and is shown on a log10 scale (x axis). Vertical stripes represent median levels for cases and controls separately. Comparison of the two sets was done with a non-parametric two-sided Mann–Whitney rank-sum test (P = 4.8 × 10−21). f, As in e, but concentrations are normalized to the number of C4 gene copies in an individual’s genome; this per-copy amount is shown on a log10 scale (x axis). Comparison of the two sets was done with a non-parametric two-sided Mann–Whitney rank-sum test (P = 7.6 × 10−9).

Extended Data Table 1 Imputation accuracy for C4 copy numbers in European ancestry and African American haplotypes
Full size table
Extended Data Table 2 Frequency of common C4 alleles and their LD-based correlation with HLA alleles in European ancestry and African American cohorts
Full size table
Extended Data Table 3 Results of association analyses of SLE risk against C4 variation, HLA alleles, and/or rs2105898 in European ancestry and African American cohorts
Full size table

Supplementary information

Supplementary Information

This file contains Supplementary Note 1, detailing fine mapping of an independent association signal in the MHC class II region, and Supplementary Note 2 discussing sex bias of C3 and C4 gene expression across human tissues.

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kamitaki, N., Sekar, A., Handsaker, R.E. et al. Complement genes contribute sex-biased vulnerability in diverse disorders. Nature 582, 577–581 (2020). https://doi.org/10.1038/s41586-020-2277-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41586-020-2277-x

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing