| Common human diseases, like diabetes, cancer, and heart disease, represent a major health burden in our modern world. To date, very little of the genetic predisposition for these complex diseases has been explained. Comprehensive association studies empowered by knowledge of linkage disequilibrium offer a powerful approach for locating common variants that influence disease. I took a two-pronged approach to better understand the search for genes that contribute to complex human diseases. First, I characterized fundamental issues in recombination (a major determinant of genetic variation) by comparing recombination hotspots in human and chimpanzee. Despite 99% identity at the level of DNA sequence, recombination hotspots were not found at the same positions in the two species. Thus, local patterns of recombination rate have evolved rapidly, in a manner disproportionate to the change in DNA sequence. Second, I tested the hypothesis that the same genes that cause rare monogenic forms of disease also carry common variants that influence risk of disease in the general population, using the MODY genes of type 2 diabetes as a model system. I characterized LD patterns and selected SNPs that efficiently capture the common variation in these genes, and genotyped those SNPs in 4,150 patients and controls from Sweden, Finland and Canada. Nominally significant SNPs were then genotyped in an additional 4,400 subjects from North America and Poland. None of the results remained significant upon replication, indicating that common variants in the MODY genes are not likely to play a role in type 2 diabetes. In summary, my work has contributed to understanding the underlying structure of genetic variation in the human genome and how this knowledge can be leveraged to ask questions about which genes contribute to human disease. |
