Using DNA Structure to Identify the Genetic Contributors to Complex Diseases
Genome-wide association studies identify genomic regions associated with disease. To identify the specific functional variants within these regions, we must tease out causal associations from correlational associations. Genomic fine-mapping studies often leverage annotation data to prioritize functional variants. However, many existing annotation resources lack information for novel variants, are uninformative for non-coding regions, and are under-representative of global populations. Dr. Ainsworth’s research developed a novel annotation source, sequence-dependent DNA topology, as a prioritization metric for fine-mapping. The link between DNA structure and function are well-documented; and as an inherent property of DNA, it is applicable to any genomic region. Her team is focused on 13 established features of DNA topology, such as Helix Twist and Minor Groove Width. Their past work found that most human genetic variation conserves topology (causing minimal shifts in DNA structure), and thus we can leverage the magnitude of change in DNA shape to identify potential functional variants. Currently, the team is applying the method to prioritize SNPs associated with autoimmune diseases (e.g., lupus, juvenile arthritis), various cancers, end-stage renal disease, obesity, diabetes, and gene expression.
Team members: Hannah Ainsworth (PI), Timothy Howard (Department of Biochemistry), Carl Langefeld (Department of Biostatistics and Data Science), and WFU student Yaomin Wang.