Table 1.

What accounts for the genetic ‘dark matter’ in cancer studies?^a

Reason	Ability of the different study designs to address these reasons
	Population-based case-control studies	Family-based association studies	Genetic linkage studies in pedigrees
Biased phenotype definition and ascertainment	Modest and/or Poor b	Good and/or Modest b	Good and/or Modest b
Insufficient sample size resulting in low power	Good	Modest	Poor
Epistatic (gene–gene) interactions	Modest c	Modest c	Good and/or Modest c
Gene–environment interactions	Poor	Modest c	Good and/or Modest c
Differential effects in different populations	Poor	Poor	Good
Incomplete genome coverage for common variants	Good	Good	Good and/or Modest d
Effects of rare alleles	Poor	Poor	Good
Parent-of-origin specific effects	Poor	Good and/or Poor	Good

^aPotential reasons explaining the genetic dark matter and the ability of different study designs to address them.

^bDependent on the type of cancer and on clinical/pathological ascertainments that are carried out; some types of cancers, e.g., liver cancer, are particularly prone to misclassification if histology of the tumor samples are not available, since the liver is a common site of cancer.

^cDependent on the strength of the interaction, here for relatively strong interactions.

^dIn pedigree studies, the reduced numbers of genetic recombinations determine a high number of redundant co-segregating genetic markers and, thus, high-density coverage by SNP-arrays does not allow fine mapping.