Common traits with complex inheritance patterns have both genetic and environmental causes. Type 2 diabetes is a complex metabolic disorder with a strong genetic component. As a postdoctoral fellow at the NHGRI, Karen Mohlke and her collaborators used genome-wide approaches to localize diabetes-susceptibility genes. Major areas of focus have been on chromosomes 20 and 22 as well as the mitochondrial genome. They recently reported that noncoding nucleotide variants near the Hepatocyte Nuclear Factor 4-alpha (HNF4A) gene are associated with increased susceptibility to type 2 diabetes. At UNC the Mohlke lab is studying HNF4A to identify the underlying disease alleles and to understand the biological function of these alleles.

HNF4A diabetes-susceptibility locus
The population-based genetic epidemiology studies used to identify the HNF4A region cannot definitively identify the actual susceptibility alleles. This region contains many possible susceptibility alleles, more of which will be discovered by additional sequencing and genotyping of newly discovered single nucleotide polymorphisms (SNPs). To determine which alleles are biologically relevant to diabetes requires a biological approach, including testing allelic effects on gene expression and function in cultured cells and mice. Comparative genomics is being used to prioritize alleles; for example, SNPs located in sequences conserved across ten species are more likely to have a relevant function.

Ultimately, the lab will create mouse models to compare high-and low-risk alleles in a whole-animal setting. Mice harboring the risk allele or haplotype will be used to examine interactions with diet, other environmental factors, and additional genes that may be relevant to diabetes.

Genetics of other complex traits
The Mohlke lab will also study the role of genes in other common, complex traits through positional cloning approaches. Currently, they are identifying collaborators and new traits to examine.