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Overview
The regulation of gene expression is critical for establishing and maintaining the diverse cell types of the human body. Genes with critical cellular functions are frequently regulated through a circuit involving multiple regulatory elements that are brought within physical proximity by DNA folding. These complex regulatory circuits are hotspots for genetic predisposition to disease. In order to interpret the genetic variation that lies in these regions, it is essential to understand of how multiple regulatory elements cooperate to control target gene expression.
Identifying Pathogenic Cell Types
The Corradin lab leverages the complexity of gene regulation in order to aid the interpretation of genetic variation that contributes to human disease. We developed an approach which utilizes the 3-dimensional organization of chromatin to assess the contribution of genetic variants to disease risk.
This approach evaluates variants that are physically linked to the same target gene cooperatively, without assumption of additivity. This allows us to assess all of the regulatory elements that control a gene within a given cell type for contribution to disease risk.
We then utilize these results to identify the cell type in which dysregulation of the target gene contributes to disease risk.
In our studies of multiple sclerosis our approach increases total heritability identified by 3-5 fold. This approach has yielded several unexpected predictions such as risk loci that act through dysregulation of gene expression in oligodendrocytes, rather than T cells.
Substance Abuse Disorders
Addition to opioids and substance abuse disorders are one of the most urgent public health crises in the US, with drug overdose being the leading cause of accidental death. 8-10% of individuals prescribed an opioid develop opioid use disorder.
Genetics plays a major role in defining this variability. Opioid addiction is estimated to be 60% heritable, however the variants and genes that define this heritability have remained elusive.
Delineating the genes, pathways, and cellular phenotypes that define risk to substance abuse disorders is critical to furthering our understanding of these disorders.
Our lab combines post-mortem tissue studies with iPS-derived astrocytes, microglia, oligodendrocytes and dopaminergic neurons to further our understanding of the genetic and epigenetic variation that contributes to susceptibility to substance abuse disorders.