Spatial & Functional
Genomics Affinity Group

Metabolic disease

We have already addressed the most significant GWAS finding in type 2 diabetes reported to date, namely genetic variation within the transcription factor 7-like 2 (TCF7L2) gene, which Struan Grant first described in 2006. Given that the type 2 diabetes genetics community widely consider the T allele of the intronic single nucleotide polymorphism (SNP), rs7903146, within TCF7L2 to be the causal variant at this locus, we utilized chromatin conformation capture and CRISPR/Cas9 genome editing techniques to target this specific genomic region. As a consequence, we have compelling evidence that the actual culprit gene at this locus is in fact 'acyl-CoA synthetase long chain family, member 5' (ACSL5). Given we already have a dedicated infrastructure in place to conduct such 'variant to gene mapping' efforts, our team is now working on an NIH funded effort to determine how additional recently uncovered type 2 diabetes GWAS-implicated loci affect the expression and function of specific genes through the use of key cutting-edge molecular biology approaches. We are now scaling up this effort in type 2 diabetes to similarly tackle other established loci.

In addition, obesity is a major risk factor for type 2 diabetes, which in turn has serious complications including accelerated development of cardiovascular disease. Given the expected global increase in the prevalence of childhood obesity, prevention of this disease and its serious complications must be addressed in order to reduce individual morbidity and the economic burden on society. We are applying our battery of methods as part of an NIH-funded effort in order to elucidate the genomic underpinnings of pediatric adiposity.

Furthermore, we are employing similar approaches to address bone accretion during growth, which can result in suboptimal peak bone mass and bone fragility in older adulthood. Osteoporosis has a strong heritable component, and pediatric studies may be more effective in distilling the genetic component in this complex disease, because duration of environmental exposure has been less. We are using our advanced techniques to extract novel information about bone structural strength and quality, along with high resolution '3D Genomics' and CRISPR based techniques to pinpoint causal genetic variants and corresponding effector gene(s) contributing to pediatric bone phenotypes.