Evaluating the Potential of Younger Cases and Older Controls Cohorts to Improve Discovery Power in Genome-wide Association Studies of Late-onset Diseases

For more than a decade, genome-wide association studies have been making steady progress in discovering the causal gene variants that contribute to late-onset human diseases. Polygenic late-onset diseases in an aging population display the risk allele frequency decrease at older ages, caused by individuals with higher polygenic risk scores becoming ill proportionately earlier and bringing about a change in the distribution of risk alleles between new cases and the as-yet-unaffected population. This phenomenon 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, while for late-onset diseases with relatively lower prevalence and heritability, exemplified by cancers, the effect is significantly lower. Computer simulations have determined that genome-wide association studies of the late-onset polygenic diseases showing high cumulative incidence together with high initial heritability will benefit from using the youngest possible age-matched cohorts. Moreover, rather than using age-matched cohorts, study cohorts combining the youngest possible cases with the oldest possible controls may significantly improve the discovery power of genome-wide association studies.