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Cited by 238Systemic Lupus Erythematosus ResearchComplement system in diseasesGenetic Associations and Epidemiology

Complement genes contribute sex-biased vulnerability in diverse disorders

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Schizophrenia Working Group of the Psychiatric Genomics Consortium, Kamitaki, Nolan, Sekar, Aswin, Handsaker, Robert E., de Rivera, Heather, Tooley, Katherine, Morris, David L., Taylor, Kimberly E. +16 more·2020·Nature
DOI 10.1038/s41586-020-2277-xPMC PMC7319891
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Abstract

Many common illnesses differentially affect men and women for unknown reasons. The autoimmune diseases lupus and Sjögren’s syndrome affect nine times more women than men 1,2 , whereas schizophrenia affects men more frequently and severely 3–5 . All three illnesses have their strongest common-genetic associations in the Major Histocompatibility Complex (MHC) locus, an association that in lupus and Sjögren’s syndrome has long been thought to arise from HLA alleles 6–13 . Here we show that the complement component 4 ( C4 ) genes in the MHC locus, recently found to increase risk for schizophrenia 14 , generate 7-fold variation in risk for lupus (95% CI: 5.88-8.61; p < 10 −117 in total) and 16-fold variation in risk for Sjögren’s syndrome (95% CI: 8.59-30.89; p < 10 −23 in total), with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia, greatly reduced risk for lupus and Sjögren’s syndrome. In all three illnesses, C4 alleles acted more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for lupus and 31-fold variation in risk for Sjögren’s syndrome in men (vs. 6-fold and 15-fold among women respectively) and affected schizophrenia risk about twice as strongly in men as in women. At a protein level, both C4 and its effector (C3) were present at greater levels in men than women in cerebrospinal fluid ( p < 10 −5 for both C4 and C3) and plasma among adults ages 20-50 15–17 , corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help explain the larger effects of C4 alleles in men, women’s greater risk of SLE and Sjögren’s, and men’s greater vulnerability in schizophrenia. These results nominate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

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Authors
Schizophrenia Working Group of the Psychiatric Genomics Consortium, Kamitaki, N., Sekar, A., Handsaker, R. E., de Rivera, H., Tooley, K., Morris, D. L., Taylor, K. E., Whelan, C. W., Tombleson, P., Loohuis, L. M. O., Boehnke, M., Kimberly, R. P., Kaufman, K. M., Harley, J. B., Langefeld, C. D., Seidman, C. E., Pato, M. T., Pato, C. N., Ophoff, R. A., Graham, R. R., Criswell, L. A., Vyse, T. J., & McCarroll, S. A.
Affiliations
  • Broad Institute (US)
  • King's College London (GB)
  • University of California, San Francisco (US)
  • University of California, Los Angeles (US)
  • University of Michigan (US)
  • University of Alabama at Birmingham (US)
  • Cincinnati Children's Hospital Medical Center (US)
  • Wake Forest University Health Sciences (US)
  • Brigham and Women's Hospital (US)
  • SUNY Downstate Health Sciences University (US)
  • Genentech (US)
Corresponding author
  • Kamitaki, Nolan
  • Vyse, Timothy J.
  • McCarroll, Steven A.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2020-05-11
Volume
582
Issue
7813
Pages
577-581
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-020-2277-x
PMC
PMC7319891
OpenAlex
W3021345946
Cited by
238
References
3
Citations by year
2026: 20 · 2025: 34 · 2024: 34 · 2023: 45 · 2022: 36 · 2021: 48 · 2020: 20
FWCI
28.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
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Funders
  • NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
  • National Institute for Health and Care Research (NIHR200756, PDA/02/06/016)
  • King's College London
  • Lundbeckfonden (R155-2014-1724, R302-2018-2155, R248‐2017‐2003)
  • Stanley Center for Psychiatric Research, Broad Institute
  • Medical Research Council (MR/L023784/2, MR/P005748/1, MR/L002604/1, MR/L010305/1, MR/T04604X/1)
  • National Institute of Mental Health (U01MH105641, U01MH105653, R01MH085548, R01MH104964, MH105641, MH105653, P50MH112491, R01MH123451)
  • National Human Genome Research Institute (R01HG006855, R56HG006855, HG006855, MH105653)
  • National Institute of Allergy and Infectious Diseases (R01AI024717)
Topics
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
complement system, complement C4, C4A, C4b, sex differences, schizophrenia, systemic lupus erythematosus, Sjögren's syndrome, major histocompatibility complex, HLA, genetic susceptibility, cerebrospinal fluid, plasma, autoimmune disease
MeSH terms
Adult, Alleles, Complement C3, Complement C4, Female, Haplotypes, HLA Antigens, Humans, Lupus Erythematosus, Systemic, Major Histocompatibility Complex, Male, Middle Aged, Sex Characteristics, Sjogren's Syndrome, Genetic Predisposition to Disease, Young Adult

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