Genetic and modifiable risk factors combine multiplicatively in common disease.

Alleles predisposing to common diseases can be carried safely in large numbers, but few additional ones lead to sharp risk increments. Here, we describe exponential functions by which risk alleles combine interchangeably but multiplicatively with each other and with modifiable risk factors to affect prevalence. Our data suggest that the biological systems underlying these diseases are modulated by hundreds of genes but become only fragile when a narrow window of total risk, irrespective of its genetic or environmental origins, has been passed.