The Genetic and Environmental Bases of Complex Human-Disease: Extending the Utility of Twin-Studies

Making only the assumption that twins are representative of the population from which they are drawn, we here develop a simple mathematical model (using widely available epidemiological information) that sheds considerable light on the pathogenesis of complex human diseases. Specifically, for the case of multiple sclerosis (MS), we demonstrate that the vast majority of patients (≥94%), possibly all, require genetic susceptibility in order to get MS. Nevertheless, only a tiny fraction of the population (≤2.2%) is actually susceptible to getting this disease; a finding which is highly consistent in all of the studied populations across both North America and Europe. Men are more likely to be susceptible than women although susceptible women are more than twice as likely to actually develop MS compared to susceptible men (i.e., they have a greater disease penetrance). This is because women are more responsive to the environmental factors involved in MS pathogenesis than men. These differences account for the current gender-ratio (3∶1, favoring women) and also for the increasing incidence of MS in women around the world. By contrast, the most important genetic marker for MS susceptibility (DRB1*1501) influences the likelihood of susceptibility but not the penetrance of the disease. Nevertheless, even for this major susceptibility allele, only a very small fraction of DRB1*1501carriers (<5%) are susceptible to getting MS and for only a minority of MS patients (∼41%) does this allele contribute to their susceptibility. Moreover, each copy of this allele seems to make an independent contribution to susceptibility. Finally, at least three environmental events are necessary for MS pathogenesis and, during the course of their lives, the large majority of the population (≥69%) experiences an environmental exposure, which is sufficient to produce MS in, at least, some susceptible genotypes. Also, susceptible men (compared to susceptible women) have a lower threshold, a greater hazard-rate, or both in response to the environmental factors involved in MS pathogenesis.