Our group studies the genetic basis and molecular mechanisms of complex disease, in particular type 1 and 2 diabetes.  We employ a diverse series of techniques in computational and molecular genetics, and that span the fields of statistical human genetics, computational biology and method development, genomics and epigenomics, and molecular biology.

Some research questions we are currently interested in include:

What are the transcription factors through which genetic variants alter disease-relevant regulatory networks?


Recent studies have demonstrated that many variants influencing both type 1 and type 2 diabetes likely alter transcriptional regulatory processes in key tissues.  We are interested in identifying and characterizing the transcription factors (TFs) through which these variants operate.  These studies include identifying both variants altering TF expression and function as well as variants altering TF binding.  We are then interested in understanding the regulatory programs and gene networks these TFs control and how perturbations to these networks broadly alter diabetes risk.

How do regulatory variants act independently and jointly to alter the function of cell-type accessible chromatin domains?


Organization of chromatin accessibility is a critical component of cell type identity and maintenance.  Studies by our group and collaborators as well as others have demonstrated that accessible chromatin sites are highly clustered around genes involved in cell-type identity.  We are interested in understanding how genetic variation alters regulatory activity in these chromatin domains and how multiple regulatory variants may act coordinately to alter gene expression in diabetes-relevant cell-types.

What are the physiological and pleiotropic effects of regulatory variation acting in specific cell-types, including during development and upon stimulus?

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Subsets of genomic loci act through different physiological mechanisms to influence diabetes risk.  For example, many T2D loci influence insulin secretion and fasting glucose, whereas others influence insulin resistance and fasting insulin.  Furthermore, many loci influencing diabetes are pleiotropic with other complex diseases such as cancer, cardiovascular disease, and neurodegenerative disease.  We are interested in mapping the cell-type regulatory mechanisms of these loci to understand how they influence both diabetes as well as  intermediate phenotypes and other diseases.

What are the genomic mechanisms of how individual loci influence disease risk?

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Each diabetes risk locus entails a causal mechanism through which genetic variants alter diabetes pathophysiology.  We are interested in studying the mechanisms of specific loci, through which we hope to gain unique insight into how and why these genes are involved in diabetes risk.  Through this we also seek to explore the breadth of ways through which the genome can be altered , leading to basic insights into gene regulation.


How do disease risk mechanisms differ across populations and ethnicities?

Genetic risk and pathophysiology of diabetes differs greatly across populations and ethnicities. We are interested in understanding the mechanistic basis for these population differences in diabetes risk, for example the relative contribution of genetic variation altering key cell types and TFs.