Future Preventive Gene Therapy of Polygenic Diseases from a Population Genetics Perspective
thesisposted on 08.07.2020 by Roman Teo Oliynyk
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Abstract: With the accumulation of scientific knowledge of the genetic causes of common diseases and the continuous advancement of gene-editing technologies, gene therapies to prevent polygenic diseases may soon become possible. This research assesses the population genetic consequences of such therapies. This research commenced by quantifying the risk of polygenic late-onset diseases. Computer simulations of population age progression under the assumption that relative disease liability remains proportionate to individual polygenic risk have demonstrated that individuals with higher polygenic risk scores will become ill and be diagnosed proportionately earlier, bringing about a change in the distribution of risk alleles between new cases and the as-yet-unaffected population in every subsequent year of age. Consequently, genome-wide association studies of any polygenic late-onset diseases that display both high cumulative incidence at an older age and high initial familial heritability will show diminishing discovery power when they use progressively older age-matched cohorts. Such studies may benefit from using the youngest possible case cohorts, preferably matched with the oldest possible controls. Using these results as a foundation, computer simulations of preventive gene therapies were performed, emulating editing true causal alleles into naturally occurring neutral states of the nucleotides. The simulations demonstrated that such therapies would lower the prevalence of polygenic early- to middle-age-onset diseases in proportion to the decreased population relative risk attributable to the edited alleles. The outcome manifests differently for polygenic late-onset diseases, for which the therapies would result in delayed disease onset and decreased lifetime risk, however, the lifetime risk would increase again with increasing life expectancy of the population, which is a likely consequence of such therapies. The simulations demonstrated that even if significant heterogeneity in the alleles responsible for polygenic diseases existed between populations, the outcomes of preventive gene therapies would not be impeded. If gene therapies that prevent heritable diseases were applied on a large scale, the decreasing frequency of risk alleles in populations would reduce the disease risk or delay the age of onset, even if only a fraction of the population received such therapies. With ongoing population admixture, all groups would benefit over generations.