Are Rare Variants Responsible for Susceptibility to Complex Diseases? Jonathan K. Pritchard  The American Journal of Human Genetics  Volume 69, Issue 1, Pages 124-137 (July 2001) DOI: 10.1086/321272 Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 1 Examples of the probability distribution of the overall frequency of susceptibility alleles at a locus (from Wright’s formula). In the upper plot, σ=0; in the lower plot, σ=12.0. Parameter values: βS=3.0 (solid lines); βS=1.0 (dotted lines); βS=0.1 (dashed lines); βN=0.01 throughout. Notice that the vertical scale differs by a factor of five between the plots. In the upper plot, virtually all of the probability mass is on values near 0 or 1 (see table 1). The American Journal of Human Genetics 2001 69, 124-137DOI: (10.1086/321272) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 2 Contribution to the additive genetic variance as a function of allele frequency. The plot shows how much of the (expected) additive genetic variance is due to alleles of a given frequency. The vertical axis is in units of 2δ2, where δ is the marginal increase in penetrance caused by each susceptibility allele. The integral of each curve equals the expected additive genetic variance. The lines are labeled with the assumed values of σ: 0.0, 4.0, 12.0, 20.0, and 30.0; mutation rates are βS=1.0, βN=0.01 for all. The American Journal of Human Genetics 2001 69, 124-137DOI: (10.1086/321272) Copyright © 2001 The American Society of Human Genetics Terms and Conditions

Figure 3 Probability distributions of the overall frequency of susceptibility alleles at each locus, under the multilocus model described in the text. In each plot, the solid line labeled “0” shows the unconditional distribution of allele frequencies. The lines labeled “1”,…,“5” show the frequency distributions at the five loci that contribute the most to the sibling recurrence risk: that is, line “i” gives the frequency distribution at the locus with the ith largest value of λs. Parameters: (top) K=0.01, Λs=10.0, L=5, and δˆ=.02; (bottom) K=0.0004, Λs=75.0, L=100, and δˆ=.0005. The American Journal of Human Genetics 2001 69, 124-137DOI: (10.1086/321272) Copyright © 2001 The American Society of Human Genetics Terms and Conditions