Age-related late-onset disease heritability patterns and implications for genome-wide association studies.

Roman Teo Oliynyk

doi:10.7717/peerj.7168

Abstract

Genome-wide association studies (GWASs) and other computational biology techniques are gradually discovering the causal gene variants that contribute to late-onset human diseases. After more than a decade of genome-wide association study efforts, these can account for only a fraction of the heritability implied by familial studies, the so-called “missing heritability” problem. Computer simulations of polygenic late-onset diseases (LODs) in an aging population have quantified the risk allele frequency decrease at older ages caused by individuals with higher polygenic risk scores (PRSs) becoming ill proportionately earlier. This effect is most prominent for diseases characterized by high cumulative incidence and high heritability, examples of which include Alzheimer’s disease, coronary artery disease, cerebral stroke, and type 2 diabetes. The incidence rate for LODs grows exponentially for decades after early onset ages, guaranteeing that the cohorts used for GWASs overrepresent older individuals with lower PRSs, whose disease cases are disproportionately due to environmental causes such as old age itself. This mechanism explains the decline in clinical predictive power with age and the lower discovery power of familial studies of heritability and GWASs. It also explains the relatively constant-with-age heritability found for LODs of lower prevalence, exemplified by cancers.

Highlights

Throughout the ages, late-onset diseases (LODs) were considered the bane of the lucky few who survived to an advanced age
Low-effect-size genetic architecture scenario The simulation results for the eight analyzed LODs are presented
This research was conducted with the goal of establishing whether any of the observational phenomena, including decreasing heritability with age for some notable LODs and the limited success of LOD Genome-wide association studies (GWASs) discovery, can be explained by changes in the allele proportions between cases and controls due to the higher odds of more-susceptible individuals being diagnosed at an earlier age

Summary

Introduction

Throughout the ages, late-onset diseases (LODs) were considered the bane of the lucky few who survived to an advanced age. Over the last couple of centuries, continuous improvements in sanitation, life and work environments, vaccinations, disease prevention, and medical interventions have extended the average life expectancy by decades. With a growing fraction of the population being of advanced age, the leading causes of mortality are heart disease, cancer, respiratory disease, stroke, and notably Alzheimer’s disease (AD) and other dementias (Murphy et al, 2017). The need—and with it, the effort being made—to determine the causes of LODs is ever increasing, and one of. Age-related late-onset disease heritability patterns and implications for genome-wide association studies.

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