Complement genes contribute sex-biased vulnerability in diverse disorders

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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-+ .

Title: Complement genes contribute sex-biased vulnerability in diverse disorders
Author: Schizophrenia Working Grp Psychiat; Kamitaki, Nolan; Sekar, Aswin; Handsaker, Robert E.; McCarroll, Steven A.; Eriksson, Johan; Palotie, Aarno; Daly, Mark; Paunio, Tiina; Pietiläinen, Olli
Contributor: University of Helsinki, Clinicum
University of Helsinki, Centre of Excellence in Complex Disease Genetics
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, HUS Psychiatry
University of Helsinki, Center for Population, Health and Society
Date: 2020-06-25
Language: eng
Number of pages: 25
Belongs to series: Nature
ISSN: 0028-0836
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.
3111 Biomedicine

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