Identify new genetic loci associated with complex diseases and traits

To identify genetic variants that confer disease susceptibility or influence variability in related traits, we conduct genome-wide association studies (GWAS) in human population studies.  In recent years, we and our collaborators have used this approach to identify hundreds of new genetic loci associated with type 2 diabetes, obesity, cholesterol levels, metabolic traits, and cardiovascular risk factors. Large-scale meta-analyses and other multidisciplinary collaborations are key to many of these discoveries. We also study how genetic variants interact with environmental factors to influence the underlying biology of complex diseases and traits.

Characterize disease- and trait-associated variants

Loci identified by GWAS usually contain many variants in strong linkage disequilibrium with each other, and the genes responsible for most GWAS loci are unclear. We use computational approaches to identify candidate genes and candidate variants, especially at loci with putative regulatory mechanisms. Genome-wide data sets containing information about gene expression, chromatin structure, transcription factor binding, and epigenetic marks in human cells are important resources for identifying genes and regulatory regions. Using experimental evidence of open chromatin, histone modifications, and transcription factor binding sites in disease-relevant cell lines and tissues, we seek to identify trait-associated variants likely to regulate gene regulation.

Investigate the functional mechanisms underlying genetic associations

For most of the new loci identified by association studies, the underlying functional mechanisms remain unknown. Determining the biological basis for the associations of genetic loci with complex diseases and traits will improve our general scientific understanding of pathways contributing to disease etiology. We employ molecular and cellular biology techniques to identify the functional variant(s) and gene(s) at these loci, explain the molecular mechanisms linking functional variant(s) to gene(s), and explain the biological mechanisms linking gene(s) to metabolic traits.