Complement genes contribute sex-biased vulnerability in diverse disorders

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dc.contributor.author Schizophrenia Working Grp Psychiat
dc.contributor.author Kamitaki, Nolan
dc.contributor.author Sekar, Aswin
dc.contributor.author Handsaker, Robert E.
dc.contributor.author McCarroll, Steven A.
dc.contributor.author Eriksson, Johan
dc.contributor.author Palotie, Aarno
dc.contributor.author Daly, Mark
dc.contributor.author Paunio, Tiina
dc.contributor.author Pietiläinen, Olli
dc.date.accessioned 2021-01-25T09:54:02Z
dc.date.available 2021-12-18T03:45:40Z
dc.date.issued 2020-06-25
dc.identifier.citation Schizophrenia Working Grp Psychiat , Kamitaki , N , Sekar , A , Handsaker , R E , McCarroll , S A , Eriksson , J , Palotie , A , Daly , M , Paunio , T & Pietiläinen , O 2020 , ' Complement genes contribute sex-biased vulnerability in diverse disorders ' , Nature , vol. 582 , no. 7813 , pp. 577-+ . https://doi.org/10.1038/s41586-020-2277-x
dc.identifier.other PURE: 159512958
dc.identifier.other PURE UUID: c6fdba62-7216-4c1c-a4cf-364409ffbe4d
dc.identifier.other WOS: 000585013200013
dc.identifier.other ORCID: /0000-0002-2527-5874/work/97266539
dc.identifier.uri http://hdl.handle.net/10138/325153
dc.description.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 Sjogren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women(2). All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjogren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus(3-6). 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 schizophrenia(7), generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjogren'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 Sjogren'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 Sjogren'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 plasma(8,9) 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 Sjogren'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.format.extent 25
dc.language.iso eng
dc.relation.ispartof Nature
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject SYSTEMIC-LUPUS-ERYTHEMATOSUS
dc.subject SJOGRENS-SYNDROME
dc.subject SUSCEPTIBILITY VARIANTS
dc.subject DEFICIENCY STATES
dc.subject MOLECULAR-BASIS
dc.subject C4 DEFICIENCY
dc.subject COPY-NUMBER
dc.subject RISK
dc.subject MHC
dc.subject AUTOANTIBODIES
dc.subject 3111 Biomedicine
dc.title Complement genes contribute sex-biased vulnerability in diverse disorders en
dc.type Article
dc.contributor.organization Clinicum
dc.contributor.organization Johan Eriksson / Principal Investigator
dc.contributor.organization Department of General Practice and Primary Health Care
dc.contributor.organization Helsinki University Hospital Area
dc.contributor.organization Centre of Excellence in Complex Disease Genetics
dc.contributor.organization Aarno Palotie / Principal Investigator
dc.contributor.organization Institute for Molecular Medicine Finland
dc.contributor.organization Genomics of Neurological and Neuropsychiatric Disorders
dc.contributor.organization HUS Psychiatry
dc.contributor.organization Department of Psychiatry
dc.contributor.organization Center for Population, Health and Society
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1038/s41586-020-2277-x
dc.relation.issn 0028-0836
dc.rights.accesslevel openAccess
dc.type.version acceptedVersion

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