About 5% of cases of colorectal cancer (CRC) are associated with inherited, dominant, familial mendelian susceptibility, especially FAP (familial adenomatous polyposis), caused by severely deleterious highly penetrant mutations in the APC gene, and HNPCC (hereditary nonpolyposis colorectal cancer), caused by mutations in mismatch repair genes (see ref. 18 for an example). Another 20–30% of cases are thought to be due to inherited susceptibility that is ‘multifactorial’, namely, associated with much lower penetrance variants that do not give rise to clear-cut familial patterns of inheritance. An important role for rare variants in inherited multifactorial susceptibility to colorectal cancer was first suggested by the effects of rare missense variants in APC19,20. The biggest gap in our knowledge of the inherited susceptibility to colorectal cancer—as also for essentially all the relatively common chronic diseases—concerns the 20–30% of cases that are multifactorial. It is that gap which WGAS and rare variant studies aim to fill.
