The impact of age on genetic risk for common diseases
Fig 6
Models for a decreasing influence of genetic risk with age.
(A) A threshold model, in which each individual has a disease “liability” which evolves over age. Disease onset occurs when liability crosses a threshold. The upper panel shows example trajectories, where genetic risk alters only the liability baseline. The middle panel is a schematic representation of a simulation in which genetic risk affects developmental pathways at birth, while non-genetic risk accumulates over time. The lower panel shows an estimation of the effect size from a simulated dataset of UK Biobank sample size (see S1 Supplemental Methods). (B) Interactions between genetic and environmental risk factors can create a distribution of effect sizes for a specific genotype. The upper panel shows example trajectories, where the environment influences the slope of the trajectory. The middle panel shows illustrative examples of the liability distributions among individuals at different ages. Those individuals at highest risk (with both the risk allele and risk environment) enter disease earlier, diluting the apparent effect size at a later age. The lower panel shows simulation results under such a model using realistic parameters from UK Biobank (see S1 Supplemental Methods).