T2D is a growing health problem with 347 million people affected worldwide. It is a complex disorder affected by multiple environmental and genetic components. My laboratory uses a genetic rat model, outbred heterogeneous stock (HS) rats, to identify relatively small chromosomal regions that play a role in diabetes related phenotypes.
HS rats are outbred from eight inbred rat strains such that the chromosomal make-up of the progeny is a mosaic of the founding inbred strains. This enables the mapping of chromosomal loci to only 2-4 Megabases, significantly decreasing the number of possible candidate genes within each region. We have used HS rats to identify a region on rat chromosome 1 that plays a role in glucose and insulin levels. Using expression and sequence data we have identified Tpcn2 as the likely causal gene within this region and shown that Tpcn2 likely plays a role in regulating insulin levels in humans. We are currently using HS rats to identify additional loci that play a role in metabolic phenotypes across the entire rat genome, coupled with RNAseq studies in liver and adipose tissue to further help us identify genes and networks that play a role in diabetes and obesity traits.
This work has allowed us to identify relatively small genomic regions for body weight and visceral adiposity and we have identified the likely causal genes and even variants that underlie these loci. Once genes are identified, we will test these genes in human cohorts as well as use rat models to understand the mechanism of disease. We are also starting studies to look at the interplay between obesity and mental health, as well as assess the role of diet on both metabolic and mental health. Finally, we have formed several collaborations with other investigators to use HS rats to study other complex traits including kidney disease and behaviors involved in drug addiction.
- Genetic of diabetes and obesity using rodent models
- Genetics of mental health
- QTL mapping
- Outbred rodents