13 May Complement Genes May Explain Sex Differences in Lupus and Schizophrenia
MedicalResearch.com Interview with:
Nolan Kamitaki PhD
Harvard Medical School
MedicalResearch.com: What is the background for this study?
Response: Previous work from our lab found that the strongest common genetic association to schizophrenia is driven in part by copy number variation of the C4 genes. Given that lupus and Sjogren’s syndrome, two autoimmune disorders, have association patterns that span the same region of the human genome, we wondered if part of the signal for these diseases may also arise from variation of C4 given that both have hypocomplementemia as a characterizing trait.
The other main finding is that these associations appear to be sex-biased, where the protection from each additional copy of the C4 gene was greater in men than in women. When we went back to the data used in the previous study from our lab association C4 variation to schizophrenia, we found that the effect was stronger in men there as well. Although the expression of C4 at the RNA level does not appear to differ between men and women, we saw that men had more C4 protein in both cerebrospinal fluid and blood plasma, suggesting that this may explain the greater genetic association in men.
MedicalResearch.com: What are the main findings?
Response: We found that in lupus case-control cohorts consisting of individuals of European ancestry and African Americans, individuals with less copies of C4 were at greater risk for developing the disease. In contrast, the HLA alleles previously identified in the literature were not associated in both populations and seemed to be driven by genetic linkage with C4 variation.
MedicalResearch.com: What should readers take away from your report?
Response: Resolving the genetic association in this region to copy number variation of the C4 gene heavily suggests that the complement pathway is a fundamental contributor to the development of these autoimmune disorders rather than an observed outcome. This should help shape our knowledge of exactly how these conditions first begin. Additionally, as our lab previously found higher complement to be a risk factor for schizophrenia, it may be worth considering this balance during treatment for these conditions.
Another takeaway is that this result suggests a molecular pathway contributing to the sex-bias in disease incidence, where women get Sjogren’s syndrome and lupus more often and earlier, while the same is true for men and schizophrenia. Knowing such pathways will help not only in understanding the disease for everyone, but also possibly when treatment should be differentiated for men and women.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: I think a big question that this raises is by exactly what mechanism this difference between men and women emerges. Our work suggests that it is not in the transcription of RNA from these genes, but is apparent at a protein level; this could suggest it occurs either during translation, post-translational processing, or in activation/removal of complement. When identified, the particular sex-biased mechanism being employed here could be a useful one to consider not only in both the treatment of complement-related diseases such as lupus or schizophrenia, but also worth noting for possible downstream effects on disease risk if being modulated by other therapies.
Another point that I think this research suggests is the strength of using cohorts spanning multiple ancestries, particularly for genetic studies where different ancestries will have varying linkage across the genome. This can be helpful to resolve genetic associations that often span multiple genes in any given ancestry, but due to differences in recombination and selection between populations, may not cover the same genomic ranges in all people.
MedicalResearch.com: Is there anything else you would like to add?
Response: No disclosures, and the only thing I’d like to add is that this was a result of a great collaboration both within our lab and with others.
Nolan Kamitaki, Aswin Sekar, Robert E. Handsaker, Heather de Rivera, Katherine Tooley, David L. Morris, Kimberly E. Taylor, Christopher W. Whelan, Philip Tombleson, Loes M. Olde Loohuis, Michael Boehnke, Robert P. Kimberly, Kenneth M. Kaufman, John B. Harley, Carl D. Langefeld, Christine E. Seidman, Michele T. Pato, Carlos N. Pato, Roel A. Ophoff, Robert R. Graham, Lindsey A. Criswell, Timothy J. Vyse, Steven A. McCarroll. Complement genes contribute sex-biased vulnerability in diverse disorders. Nature, 2020; DOI: 10.1038/s41586-020-2277-x
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