Stressful life circumstances have long been associated with negative health outcomes, including type 2 diabetes (T2D), cardiovascular disease, insomnia, anxiety, depression, and Alzheimer’s disease (AD). Susceptibility to these stress-linked disorders depends on both environmental and genetic components, and even family members living under the same stressful circumstances can vary widely in health outcomes.   

In studies exposing mice to various types of stressful social circumstances, the Stubbs Lab has shown the rapid and dramatic up- or down-regulation of genes in stress-responsive brain regions, including the homologs of genes that are strongly associated with stress-linked disorders including T2D (for an example, see the discussion of TCF7L2, above). These studies have led to the lab’s interest in genetic factors that coordinate the brain’s response to stress, with the hypothesis that they may provide key links to health disorders associated with threat, deep uncertainty, or deprivation.  

Using standard genetic tools together with novel mathematical methods developed by the Galas Lab, these two PNRI research teams used large public health databases to identify genes associated with susceptibility to disorders such as T2D and to search for genetic modifiers of those major susceptibility alleles; many of these candidate T2D modifiers are themselves associated with other stress-related diseases, especially with AD.   

Those genes and their modifiers are entry points into larger genetic networks that may act to render T2D patients particularly vulnerable or resistant to co-morbid AD. Once candidate genes are identified, Stubbs Lab members are working to confirm and further define the genetic interactions, and to identify the genetic and molecular basis for their roles in susceptibility or resilience to disease. This research group is also establishing pilot studies with relevant clinical groups to bring these results closer to afflicted patients, where they may inform diagnosis and treatment of disease.