DATE: Tuesday, April 26th, 2016
SPEAKER: Alex Marson, MD, PhD, University of California, San Francisco
Click here to view a recording of the webinar.
Type 1 diabetes (T1D) has been the subject of intensive genetic investigations, including genome-wide association studies (GWAS) that have collectively identified over 40 risk loci in the genome. Our knowledge of the genetic code provides a powerful framework to understand the deleterious effects of variants that alter protein sequence. However, almost 90% of common variants associated with T1D and other autoimmune diseases fall outside of genes, in non-coding, regulatory regions of the genome—regions previously described as ‘junk DNA.’ We still do not know how DNA variation throughout the genome, especially in non-coding regions, affects cellular pathways and contributes to T1D. We need to develop sophisticated analytic and experimental tools to delve deeper into the function of these non-coding genome elements.
We recently leveraged the latest high-density genotyping data on patients with autoimmune diseases to develop a new algorithm to fine-map the specific variants most likely to cause increased risk of disease. To interpret the biological processes affected by candidate non-coding variants, we generated a large epigenetic resource of cis-regulatory maps of specialized human cells. Comparing SNP locations with chromatin maps for 56 cell types revealed the cell type-specificities of cis-regulatory elements that coincide with fine-mapped risk for T1D and other autoimmune diseases, thus predicting pathogenic cell types. While the primary signature of T1D risk variants is in immune cell enhancers, we also found enrichment in pancreatic islet enhancers.
Moving forward, we will collaborate with nPOD to test the in vivo effects of the variants on chromatin state and gene expression in a population-based study of genotyped T cell samples sorted directly from the pancreatic lymph nodes of human organ donors with and without T1D. Understanding how causal non-coding T1D risk variants disrupt key gene programs controlling cell function will provide critical information linking genetic variation to cellular pathways. This knowledge could accelerate development of targeted therapeutic approaches.
- REFERENCES: Farh and Marson et al. (2015) Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature, 518, 337-343.