Copy number variation at the complement C4 locus is associated with risk for multiple sclerosis

Background: The complement system has been suspected to play a role in multiple sclerosis (MS) due to presence of complement activation products in MS lesions. Objective: We sought to understand whether variation in the complement component 4 (C4) gene is associated with MS. Methods: Here we used next-generation sequencing and our novel bioinformatics tool, C4Investigator, to interrogate C4 copy number variation in MS. Results: We found higher overall copy number of C4 in controls (p < 10(-16), odds ratio (OR) = 0.43, 95% confidence interval (CI): 0.37-0.49) compared to MS patients with European ancestry. Conclusion: This finding suggests that lower C4 copies confer risk for MS, similar to associations seen in other autoimmune disorders.