Olivia Corradin
Fellow, Whitehead Institute
Identifying pathogenic cell types of individual disease alleles
For the study of traits with complex etiologies that involve multiple cell types, first delineating the cell type that is altered by the presence of a disease allele is an essential step for moving from disease association to new disease insights. Here, we present a new approach to identify the pathogenic cell type of individual disease alleles. Our approach utilizes 3D chromatin structure to evaluate all enhancers that physically interact to regulate a shared target gene and assesses the impact of DNA variants within these regulatory elements. When we applied this approach to risk alleles identified for multiple sclerosis, we found many loci that act primarily in T cells, but also identified unexpected myeloid and CNS specific risk loci. This included a subset that were identified as pathogenic in oligodendrocytes. Interestingly, the target genes of these loci were enriched in the same pathway. Using chemical genetics and CRISPR-based approaches, we found that this is a dominant pathway blocking oligodendrocytes maturation and thereby the generation of new myelin. Collectively, these results demonstrate that identifying sets of disease alleles that act within the same cellular context can reveal disease critical pathways that may be obfuscated when all risk loci are evaluated together.
