The complement C4 structural diversity in bipolar disorder and schizophrenia

Background Genetic and clinical overlaps between Schizophrenia (SZ) and Bipolar disorder (BD) are remarkable with at least immune dysfunction as a common thread. Belonging to the innate arm of immune responses, the complement system encodes important molecules for: (i) immune surveillance and (ii) physiological synaptic pruning processes during childhood [1,2]. Recently, strong correlations between C4 copy number variations (CNVs) and SZ risk through complex gene rearrangements likely influencing the synaptic pruning were demonstrated [3]. The C4 component corresponds to the C4A and C4B protein isoforms encoded by loci differing only by five nucleotides and by distinct functions. The C4 genetic diversity, mainly represented by CNVs and structural size variations (long/short forms according to presence/absence of HERV-K), was demonstrated to influences the C4 protein expression [4]. Objective: We took advantage of phenotypically well-defined cohorts of BD and SZ patients to analyze the distribution of C4 structural variants as compared to healthy controls (HC). We also examined the presence of potential relationships between the C4 structural diversity and clinico-biological parameters. Methods: A total of 190 BD subjects, 97 SZ subjects and 132 HC were included in the study at Henri Mondor Hospital, Créteil, France. Digital Droplet PCR was used to determine the C4A, C4B, C4L and C4S CNVs as well as the exact C4AL, C4AS, C4BL and C4BS CNV types. The circulating serum levels of 44 cytokines and chemokines were quantified using electro-chemiluminescence. Results: We identified 44 different structural forms of C4 gene among which three were more represented: AL-AL-BL-BS (21.5 %), AL-AL-BL-BL (11.4 %) and AL-AL-BS-BS à (10.9 %). The C4 haplotypic analysis showed that the AL-AL-BL-BS haplotype was less frequent in SZ patients as compared to HC (p=0.017). We also observed in SZ patients that (i) high copy number of some C4 structural forms are correlated with a high level of some circulating cytokines (p < 0.05) and (ii) high copy number of C4B and C4BL isoforms are associated with high PANSS and CGI scores (p < 0.05). Finally, we also found that patients with early-onset BD (< 22 years old) have a higher copy number of C4A (p < 0.001). Conclusion: Overall, our findings not only suggest different C4-mediated pruning processes at work in BD and SZ but also that the C4 genetic imprinting is also involved in the well-known immune dysfunctions underlying the two disorders.