Genetic and modifiable risk factors combine multiplicatively in common disease

Background The joint contribution of genetic and environmental exposures to noncommunicable diseases is not well characterized. Objectives We modeled the cumulative effects of common risk alleles and their prevalence variations with classical risk factors. Methods We analyzed mathematically and statistically numbers and effect sizes of established risk alleles for coronary artery disease (CAD) and other conditions. Results In UK Biobank, risk alleles counts in the lowest (175.4) and highest decile (205.7) of the distribution differed by only 16.9%, which nevertheless increased CAD prevalence 3.4-fold (p p 0.94). Classical risk factors shifted effect sizes to the steep upslope of the logarithmic function linking risk allele numbers with CAD prevalence. Similar phenomena were observed in the Estonian Biobank and for risk alleles affecting diabetes mellitus, breast and prostate cancer. Conclusions 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. Graphical Abstract