Quantifying the Potential for Future Gene Therapy to Lower Lifetime Risk of Polygenic Late-Onset Diseases.

Roman Teo Oliynyk

doi:10.3390/ijms20133352

Abstract

Gene therapy techniques and genetic knowledge may sufficiently advance, within the next few decades, to support prophylactic gene therapy for the prevention of polygenic late-onset diseases. The risk of these diseases may, hypothetically, be lowered by correcting the effects of a subset of common low effect gene variants. In this paper, simulations show that if such gene therapy were to become technically possible; and if the incidences of the treated diseases follow the proportional hazards model with a multiplicative genetic architecture composed of a sufficient number of common small effect gene variants, then: (a) late-onset diseases with the highest familial heritability will have the largest number of variants available for editing; (b) diseases that currently have the highest lifetime risk, particularly those with the highest incidence rate continuing into older ages, will prove the most challenging cases in lowering lifetime risk and delaying the age of onset at a population-wide level; (c) diseases that are characterized by the lowest lifetime risk will show the strongest and longest-lasting response to such therapies; and (d) longer life expectancy is associated with a higher lifetime risk of these diseases, and this tendency, while delayed, will continue after therapy.

Highlights

In the past two decades, the human genome has been successfully sequenced
This can be ascribed to two factors that distinguish Alzheimer’s disease (AD): (1) The steepest rise of incidence rate and cumulative incidence; and (2) the highest heritability of the reviewed late-onset diseases (LODs), resulting in the highest variance according to our genetic architecture model
The lifetime risk decreased by 30% or more for AD and type 2 diabetes (T2D), by more than 66% for colorectal and lung cancer, and by 50% or more for the remaining four LODs

Summary

Introduction

In the past two decades, the human genome has been successfully sequenced. Whole genome sequencing (WGS) and genome-wide association studies (GWASs) of human genomes (as well as those of other organisms) have become an everyday occurrence [1]. As of June 2019, the OMIM Gene Map Statistics [2] compendium has listed 6436 phenotypic genetic conditions caused by 4102 gene mutations. This list includes a variety of conditions, with onsets ranging from very early to late. Early-onset Alzheimer’s disease is caused primarily by APP, PSEN1, or PSEN2 gene mutations and affects a relatively small proportion of the population, starting in their thirties, with the majority of mutation carriers being affected by the age of 65 [4]. When the medical technology becomes available, individuals who receive treatment will be effectively cured and will have no need for concern about the single specific cause of their disease

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