IJE Advance Access originally published online on July 25, 2005
International Journal of Epidemiology 2005 34(5):1129-1137; doi:10.1093/ije/dyi130
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How many genes underlie the occurrence of common complex diseases in the population?
1 National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA
2 Office of Genomics and Disease Prevention, Centers for Disease Control and Prevention (CDC), Atlanta, GA 30333, USA
3 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
4 Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada
5 Department of Epidemiology, School of Public Health, Emory University, Atlanta, GA, USA
* Corresponding author. National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention (CDC), 1600 Clifton Road, Mail-Stop E-86, Atlanta, GA 30333, USA. E-mail: qay0{at}cdc.gov
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 
20 genes are usually needed to explain 50% of the burden of a disease in the population if the predisposing genotypes are common (
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.
Keywords Epidemiology, aetiology, genes, population attributable fraction
Accepted 31 May 2005
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