Complement genes contribute sex-biased vulnerability in diverse disorders

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dc.contributor.authorKamitaki, Nolan
dc.contributor.authorSekar, Aswin
dc.contributor.authorHandsaker, Robert E.
dc.contributor.authorde Rivera, Heather
dc.contributor.authorTooley, Katherine
dc.contributor.authorMorris, David L.
dc.contributor.authorTaylor, Kimberly E.
dc.contributor.authorWhelan, Christopher W.
dc.contributor.authorTombleson, Philip
dc.contributor.authorOlde Loohuis, Loes M.
dc.contributor.authorSchizophrenia Working Group of the Psychiatric Genomics Consortium
dc.contributor.authorBoehnke, Michael
dc.contributor.authorKimberly, Robert P.
dc.contributor.authorKaufman, Kenneth M.
dc.contributor.authorHarley, John B.
dc.contributor.authorLangefeld, Carl D.
dc.contributor.authorSeidman, Christine E.
dc.contributor.authorPato, Michele T.
dc.contributor.authorPato, Carlos N.
dc.contributor.authorOphoff, Roel A.
dc.contributor.authorGraham, Robert R.
dc.contributor.authorCriswell, Lindsey A.
dc.contributor.authorVyse, Timothy J.
dc.contributor.authorMcCarroll, Steven A.
dc.contributor.authorDinan, Timothy G.
dc.contributor.funderNational Human Genome Research Instituteen
dc.contributor.funderNational Institute of Mental Healthen
dc.contributor.funderStanley Center for Psychiatric Research, Broad Instituteen
dc.contributor.funderNational Institute for Health Researchen
dc.contributor.funderNIHR Guy's and St Thomas' Biomedical Research Centreen
dc.date.accessioned2020-11-30T10:16:18Z
dc.date.available2020-11-30T10:16:18Z
dc.date.issued2020-05-11
dc.date.updated2020-11-27T11:26:06Z
dc.description.abstractMany 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.en
dc.description.sponsorshipNational Human Genome Research Institute (HG006855); National Institute of Mental Health (MH112491; MH105641; MH105653)en
dc.description.statusPeer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationKamitaki, N., Sekar, A., Handsaker, R.E. et al. (2020) 'Complement genes contribute sex-biased vulnerability in diverse disorders', Nature, 582, pp. 577–581. doi: 10.1038/s41586-020-2277-xen
dc.identifier.doi10.1038/s41586-020-2277-xen
dc.identifier.eissn1476-4687
dc.identifier.endpage581en
dc.identifier.issn0028-0836
dc.identifier.journaltitleNatureen
dc.identifier.startpage577en
dc.identifier.urihttps://hdl.handle.net/10468/10790
dc.identifier.volume582en
dc.language.isoenen
dc.publisherSpringer Nature Limiteden
dc.rights© 2020, the Authors, under exclusive licence to Springer Nature Limited. This is a post-peer-review, pre-copyedit version of an article published in Nature on 11 May 2020. The final authenticated version is available online at: https://doi.org/10.1038/s41586-020-2277-xen
dc.subjectDifferential disease vulnerabilityen
dc.subjectSchizophreniaen
dc.subjectSjögren’s syndromeen
dc.subjectSystemic lupus erythematosusen
dc.subjectSLEen
dc.titleComplement genes contribute sex-biased vulnerability in diverse disordersen
dc.typeArticle (peer-reviewed)en
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