Advantage of heterozygotes over homozygotes has been observed in many species ranging from plants to mammals. Genetic diversity within a population, often characterized by heterozygosity, is known to play an important role in conferring benefit for survival and reproduction. Further characterization of this relationship will have important implications in aging-associated disease risk prediction. Our results demonstrate that the genomic heterozygosity is associated with human healthspan, and that the relationship between higher heterozygosity and healthy aging could be explained by heterozygote advantage. We also find that individual heterozygosity rate is a significant predictor of electronic health record (EHR)-based estimates of 10-year survival probability in men but not in women, accounting for several factors including age and ethnicity. In addition, coding SNPs with the highest excess of heterozygosity in the healthy-aged cohort are enriched in genes involved in extracellular matrix and glycoproteins, a group of genes known to be under long-term balancing selection. Lack of difference in heterozygosity for low-frequency variants or disease-associated variants excludes the possibility of compensation for deleterious recessive alleles as a mechanism. Specifically, we find that only common genetic variants show significantly higher excess of heterozygosity in the healthy-aged cohort. We use healthy aging as a proxy for better health and fitness, and observe greater heterozygosity in healthy-aged individuals. Here, we hypothesize that such pattern applies to humans as well and could be a result of higher fitness in individuals with higher genomic heterozygosity. Genetic diversity is known to confer survival advantage in many species across the tree of life.
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