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INHERITANCE 249

genesis. In other populations, with different genetic linkage relations,
those same variants will associate differently with cancer rates.
Third, such studies suffer from problems common to exploratory sta-
tistical analyses: the number of variables (polymorphisms) and their
combinations greatly exceeds the number of individuals sampled. With
so many different combinations, by chance certain combinations will as-
sociate with strong differences in outcome. Although statistical meth-
ods attempt to deal with such problems, conclusions from such studies
often do not hold up in future attempts to repeat the work.
With those caveats in mind, I now compare Wu et al.’s (2006) re-
sults with a similar study. Garcia-Closas et al. (2006) analyzed 22 poly-
morphisms in seven NER genes among 1,150 bladder cancer cases and
1,149 controls. In agreement with Wu et al. (2006), Garcia-Closas et al.
(2006) found weak effects for each variant when analyzed in isolation,
but found stronger, significant effects when analyzing the interaction
between smoking and multiple NER variant sites. Garcia-Closas et al.
(2006) limited their analysis to pairs of variant NER sites, and found
that certain pairs of variants significantly increased risk in smokers.
The two studies had six NER polymorphisms in common. Four of
those polymorphisms were not particularly important in either study.
At the locus RAD23, one particular variant played a key role in Wu et al.
(2006) but, although present in Garcia-Closas et al. (2006), did not play
a key role in that study. Instead, Garcia-Closas et al. (2006) found that a
different variant site in RAD23 had significant explanatory power when
evaluating interactions between pairs of variant sites. The two studies
also shared a variant at the ERCC6 locus: that variant was important in
multisite interactions in Wu et al. (2006) but not in Garcia-Closas et al.
(2006).

CONCLUSION

Preliminary evidence suggests that risk depends on the combination
of effects at multiple variant sites. Practical sampling issues limit stud-
ies to combinations of common variants. In small samples, combina-
tions of rare variants occur too infrequently to allow study. In the pop-
ulation, more rare variants occur than common variants (Figure 11.9),
so the net contribution of multiple rare variants may be at least as great
as the combinations of common variants.