ACTR1A has pleiotropic effects on risk of leprosy, inflammatory bowel disease and atopy

Leprosy remains a leading cause of infectious disability globally. Human genetic variation is a major determinant of susceptibility to infection, including leprosy. Large-scale genetic association studies have been pivotal in advancing our understanding of leprosy biology. These studies have been performed in Chinese, Vietnamese and Indian populations, and it remains unclear whether these insights are informative of leprosy susceptibility in African populations. To address this, we performed a genome-wide association study of leprosy susceptibility in Malawi and Mali. In doing so we replicate known leprosy susceptibility loci at MHC class I and II, LACC1 and SLC29A3. Furthermore, we identify a novel leprosy susceptibility locus, which modifies expression of ACTR1A in CD4+ T cells and demonstrates pleiotropy with inflammatory bowel disease (IBD) and atopic disease. These data deepen our understanding of leprosy biology, identifying ACTR1A expression in CD4+ T cells as a determinant of leprosy disease risk, and further define the role of this ancient pathogen in the evolution of immune-mediated diseases in modern populations.