Genome-wide polygenic risk scores (PRS) can now predict complex genetic disease risk with nearly the same ability as tests for monogenic diseases. Despite this, there is no clear consensus how to incorporate PRS with other known modifiable and non-modifiable risk factors at the point of care. This challenge is further complicated by the fact that the most promising diseases for early PRS adoption (e.g., coronary artery disease, type 2 diabetes, and breast cancer) share many of the same modifiable risk factors—specifically, diet-induced obesity and drug use. Interestingly, the cause of these modifiable risk factors is at least partially genetic in most people. And while evidence for a common biological basis underlying nutrient intake and drug use in humans is growing, current clinical risk prediction models for complex genetic diseases have not incorporated any of this shared biology.