Complement Gene Variants Drive Sex-Biased Vulnerabilities in Lupus, Sjögren’s Syndrome and Schizophrenia

Summary: Variants in complement system genes produce sex-specific differences in vulnerability to autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren’s syndrome, and are also linked to schizophrenia risk.

Source: University of Alabama at Birmingham

Key Findings

Researchers report that variations in the complement component 4 genes, C4A and C4B, help explain why certain diseases affect men and women differently. Published in the journal Nature, the study shows that different combinations of C4A and C4B copy numbers generate substantial variation in risk for SLE and Sjögren’s syndrome and have opposing effects on schizophrenia risk. The same C4 alleles that increase schizophrenia risk are strongly protective against SLE and Sjögren’s syndrome. Across all three illnesses, the effects of C4 alleles are stronger in men than in women.

The Complement System and Disease

The complement system is a cascade of proteins that supports antibody function, promotes inflammation, helps clear pathogens, and removes debris from damaged human cells. Proper complement activity helps prevent autoimmunity by clearing cell debris before it provokes an immune attack. This study links inherited variation in complement genes — specifically C4A and C4B — to distinct risks for autoimmune diseases and psychiatric illness.

Genetic Background and the MHC Locus

All three conditions—SLE, Sjögren’s syndrome and schizophrenia—have long been associated with the major histocompatibility complex (MHC) on chromosome 6, a dense region of immune-regulating genes. Because the MHC spans several million base pairs and contains many tightly linked genes, identifying the specific gene variants responsible for disease associations has been challenging. This research isolates variation in C4A and C4B as significant contributors to the observed disease associations within the MHC.

Quantified Risk Differences

The investigators found that common C4 genotype combinations can produce approximately sevenfold variation in risk for SLE and sixteenfold variation in risk for Sjögren’s syndrome. C4A was generally more protective than C4B for these autoimmune diseases. By contrast, the C4 alleles previously implicated in higher schizophrenia risk were associated with markedly lower risk for SLE and Sjögren’s syndrome. When stratified by sex, the magnitude of risk variation driven by C4 combinations was greater in men than in women across all three disorders.

Sex Differences in Complement Protein Levels

At the protein level, measurements showed that adults aged 20–50 have higher concentrations of C4 and its downstream effector C3 in cerebrospinal fluid and blood plasma when they are male compared with female. This age window overlaps the periods when these illnesses most clearly show sex-biased incidence and severity: SLE and Sjögren’s syndrome are far more common in women of childbearing age, while schizophrenia tends to affect men more often and more severely in early adulthood. The study also documented an age-dependent rise in complement proteins for both sexes: men show elevated C4 and C3 earlier (around ages 20–30), while women show a later increase (closer to ages 40–50), a pattern that concentrates sex differences during the reproductive years.

Implications for Disease Biology and Treatment

These findings suggest that sex-specific complement activity contributes to differential disease vulnerability and that C4 gene variation is a key factor in this sexual dimorphism. The opposing effects of the same C4 alleles on schizophrenia versus SLE and Sjögren’s syndrome underline the complexity of targeting the complement system therapeutically. Any clinical interventions that modify complement activity will need to consider both the differing effects across diseases and the stronger genetic effects seen in men compared with women.

Study Collaboration and Authorship

The study is a multi-institutional collaboration involving authors from Harvard Medical School, Broad Institute, King’s College London, University of California campuses, University of Michigan, Cincinnati Children’s Hospital Medical Center, Wake Forest School of Medicine, State University of New York Downstate Medical Center, Genentech and the University of Alabama at Birmingham. Robert E. Kimberly, M.D., professor of medicine at UAB and director of the UAB Center for Clinical and Translational Science, is a co-author. Steven A. McCarroll, Ph.D., assistant professor of genetics at Harvard Medical School, is the corresponding author.

Funding and Acknowledgements

Support for the research was provided in part by National Institutes of Health grants HG006855, MH112491, MH105641 and MH105653, and by the Stanley Center for Psychiatric Research. At UAB, Robert Kimberly holds the Howard L. Holley Research Chair in Rheumatology.

About the Research Article

Title: “Complement genes contribute sex-biased vulnerability in diverse disorders” by Nolan Kamitaki et al., published in Nature. The study integrates genetic analysis of C4A and C4B alleles with protein-level measurements and disease incidence patterns to show how complement variation contributes to sex-biased disease vulnerability.

Media contact (UAB): Jeff Hansen, University of Alabama at Birmingham

Note: This summary is based on the authors’ published work and reported institutional materials. The image associated with the original announcement is in the public domain.