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25 10 9
Percentage of total variance 15 300 59 24 12 10
20

10

0 5
<0.02 0.02–0.05 0.05–0.10 0.10–0.20 0.20–0.30 0.30–0.40 >0.40
Variant allele frequency

Figure 11.9 The relative variance in allele frequencies for rare and common
alleles of 74 DNA repair genes. The total number of variants in each frequency
category is shown above the bars. Each rare variant contributes a small frac-
tion of the total variance, but there are many more rare than common variants.
Changes in amino acid sequence define the variants. Data collated by Mohren-
weiser et al. (2003).

cancer risk. Particularly high risk may occur when those polymorphisms
concentrate in one or more key pathways and compromise essential pro-
tective mechanisms (Han et al. 2004; Popanda et al. 2004; Cheng et al.
2005; Gu et al. 2005; Wu et al. 2006).
Wu et al. (2006) measured the frequency of 44 polymorphisms in vari-
ant DNA repair and cell-cycle control genes. They compared frequencies
in 696 patients with bladder cancer versus 629 unaffected controls. The
study focused on the increase in relative risk with a rise in the number
of variant alleles. The hypothesis was that many cases would arise in
individuals who carry a greater than average number of predisposing
polymorphisms in key pathways.
To analyze the role of multiple variants in a sample of modest size,
one must study relatively common variants. If the variants were rare,
very few individuals would carry several variants. Thus, the design of Wu
et al.’s (2006) study focuses attention on the role of multiple common
variants, without addressing how multiple rare variants may contribute
to disease. In spite of this limitation, the study is important because