A non-parametric SNP-based linkage analysis performed using the Merlin program [24] did not give significant or suggestive linkage signals (maximum LOD score of 1.62 for chr14: 27.526–29.525 Mb), further suggesting a complex mode of inheritance with possible multiple low risk susceptibility loci, rather than a risk attributable to a major gene(s).
Mutations in several moderate risk genes for e.g. RAD51C, RAD51D, and BRIP1 and multiple low risk (low penetrance) genes could account for the remaining excess familial risk.
We comprehensively summarize the current knowledge about the genetic architecture of CD, characterized by multiple low-risk variants located within diverse loci which are most likely affecting genes with immune-related functions.
In recent risk models, it has been suggested that multiple low-risk variants within the same individual may actually cause a significantly elevated risk for the carrier [ 17].
However, high-penetrance susceptibility mutations account for <6% of CRC cases; the majority of inherited variance appearing to be a consequence of the co-inheritance of multiple low-risk variants (Lichtenstein et al, 2000; Bost et al, 2001).
Because in our study multi-type HPV infection included only high-risk types, future studies should investigate multi-type HPV infection which comprises of multiple high-risk only, multiple low-risk only, and multiple with both high-and low-risk.
Two studies of this issue (Reeves et al, 2010; Wacholder et al, 2010) have reported that multiple low-risk alleles do indeed increase breast cancer risk; however, neither of them included women <50 years of age.
Failure in our study to unambiguously identify a single high-risk locus provides evidence for a model of inherited susceptibility to radiosensitivity based on the co-inheritance of multiple low-risk variants.
Failure to unambiguously identify a single locus is thus entirely compatible with the latter model of disease susceptibility, whereby disease risk is mediated by alleles conferring more modest effects, possibly through the consequence of the co-inheritance of multiple low-risk variants.
This model is consistent with the recent discovery of multiple low-risk susceptibility genes (and the failure to identify any further 'high-risk' loci by linkage) (Smith et al, 2006; Easton et al, 2007; Hunter et al, 2007; Stacey et al, 2007).
It is more plausible that there are multiple common low risk (low penetrance) genetic variants, which are associated with relatively small effects on risk in the individual, but contribute substantially to the overall risk in the population (Antoniou et al, 2002).
