BACKGROUND

Most common human diseases are due to complex interactions among multiple genetic variants and environmental risk factors. There is debate over whether variants of a relatively small number of genes, each with weak or modest individual effects, account for a large proportion of common diseases in the population, or whether a large number of rare variants with large effects underlie genetic susceptibility to these diseases. It is not clear how many genes are necessary to account for an appreciable population-attributable fraction of these diseases.

METHODS

In this analysis, we estimated the number of disease susceptibility genes needed to account for varying population attributable fractions of a common complex disease, taking into account the genotype prevalence, risk ratios for individual genes, and the model of gene-gene interactions (additive or multiplicative).

RESULTS

Very large numbers of rare genotypes (e.g. those with frequencies of 1 per 5000 or less) are needed to explain 50% of a common disease in the population, even if the individual risk ratios are large (RR = 10-20). On the other hand, only approximately 20 genes are usually needed to explain 50% of the burden of a disease in the population if the predisposing genotypes are common (> or = 25%), even if the individual risk ratios are relatively small (RR = 1.2-1.5).

CONCLUSIONS

Our results suggest that a limited number of disease susceptibility genes with common variants can explain a major proportion of common complex diseases in the population. Our findings should help focus the search for common genetic variants that provide the most important predispositions to complex human diseases.