Inherited risk for common disease

Abstract

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.