Examining how the brain controls obesity

Project title: Deconstructing Type 2 Diabetes Using Genome-Wide High-Density Multi-Tissue 'Omics' Profiling 
Institution: University of Michigan
Pathway project publications: 4
Moved from the National Institutes of Health to the University of Michigan to start first independent faculty position as Assistant Professor in late 2014

Major accomplishments:

The vast majority of genetic associations with type 2 diabetes risk occur in non-coding regions of DNA, leaving many unanswered questions: what is the target gene; what direction of effect (up- or down-regulation of the target gene) does the diabetes risk allele have; what tissue might be relevant; which of the many mutations are important; and what are the upstream regulators that mediate the regulatory effect. To address these questions we performed studies on human skeletal muscle biopsies (Scott et al. Nature Communications, 2016) and cadaveric islet samples (Varshney et al. PNAS, 2017). Integrative computational approaches allowed us to identify target genes and the direction of effect of the risk allele. Our studies have identified multiple striking patterns of upstream gene expression genetic regulators for type 2 diabetes. For example, we nominated a novel connection between rare coding variation in the islet master transcription factor RFX6 (where DNA binding domain mutations result in Mitchell-Riley syndrome, characterized by neonatal diabetes) and common non-coding variation in multiple target sites for this transcription factor (that we show are linked to type 2 diabetes). Together, these results suggest that a confluent RFX regulatory grammar plays a significant role in the genetic component of type 2 diabetes predisposition. I believe this novel and cryptic type 2 diabetes regulatory grammar will form the foundation for many future high-impact studies.

Impact statement:

Diabetes research is of great importance to me for a number of reasons. First, there is a genetic signature of type 2 diabetes in my family, so I am personally motivated to make discoveries. Second, it's exciting to be in a position that allows for my work to potentially contribute to the solution of a major health problem that affects millions of people. Third, diabetes is an incredibly complicated genetic/genomic problem that ignites my scientific interests, and therefore keeps me up very late at night. I am fortunate to spend my time working on such a stimulating and important topic.

The cohort of Pathway awardees is truly impressive and I am honored to be part of this group. I believe that my research will provide the critical links from genetic associations to target genes. Looking forward, the high-throughput biological profiling and analysis approaches supported by my Pathway award will be closely tied to disease diagnosis, prognosis, and treatment -- and will therefore have a tremendous influence on medicine.

Receiving a generous Pathway award was a career-defining moment. The funding has allowed me to obtain a position at a top-notch university, build up a strong lab, and focus on important research questions. I have the resources to hire talented people, perform high-impact studies, and, importantly, receive mentoring from the most respected people in the field. This is especially important for an early stage scientist like myself, where mentorship and collaboration are critical for success. Already I have established new collaborations with senior leaders in the community that have produced strong pilot data. The Pathway award should position me well to make a long-term contribution in diabetes research.