Complement genes contribute sex-biased vulnerability in diverse illnesses

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), whereas schizophrenia affects men more frequently and severely(2). 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 alleles of the human leukocyte antigen (HLA) genes at that locus(3–6). Here we show that the complement component 4 (C4) genes, which are also in the MHC locus and were recently found to increase risk for schizophrenia(7), 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) 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 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, 31-fold variation in risk for Sjögren’s syndrome, and 1.7-fold variation in schizophrenia risk among men (vs. 6-fold, 15-fold, and 1.26-fold among women respectively). 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(8,9) among adults ages 20–50, 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 implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.