Inherited risk for common disease

Thesis (Ph. D.)--Massachusetts Institute of Technology, Biological Engineering Division, 2007.Includes bibliographical references (leaves 149-151).Linkage disequilibrium studies have discovered few gene-disease associations for common diseases. The explanation has been offered that complex modes of inheritance govern risk for cancers, cardiovascular and cerebrovascular diseases, and diabetes. Such studies, however, depended on the untested assumption of monoallelic risk. My research advisor and I set out to investigate whether simple forms of inherited risk, monoallelic or multiallelic, could be excluded by analysis of familial risk for a common disease, such as colorectal cancer (CRC). First, we derived formulae that describe the risk for monogenic, multigenic, and polygenic possibilities of Mendelian inheritance. Next, we obtained an estimate of minimum lifetime risk for CRC of >0.26. Then, we examined the case of late-onset CRC, using the Swedish Family Cancer Database (1958-2002) to estimate the familial relative risk for CRC diagnosis at age 50 or older, and obtained an estimated range of 1.5 to 3.0. We compared this range of actual values to the ranges of expected values for monogenic, multigenic, and polygenic modes of inheritance.(cont.) We delimited bounds that can be placed on the conditions for various modes of inheritance. The key observation is that monogenic risk for CRC is included among various possibilities, and cannot be eliminated by existing observations. The arguments herein indicate that further efforts can and should be made to obtain more precise estimates of familial risk for CRC and other common forms of cancer.by Helen Banava.Ph.D

Monogenic, multigenic, and polygenic determinants of cancer risk

Thesis (S.M. in Toxicology)--Massachusetts Institute of Technology, Biological Engineering Division, 2002.Includes bibliographical references (leaf 23, 1st group).A formal series of conditions of lifetime genetic risk of cancer is explored, and algebra is provided for applications in human population genetics. Risks are considered in terms of alleles necessary and/or sufficient for carcinogenesis. Alleles are first classified with respect to their effects on reproductive fitness, and then in terms of their potential effects on carcinogenic pathways. The algebraic formulations for a series of genetic possibilities: monogenic, multigenic, and polygenic, are provided. It is expected that technology will be developed to identify and enumerate rare inherited alleles in large general and cancer proband populations.by Helen Banava.S.M.in Toxicolog