Genome-wide analysis indicates association between heterozygote advantage and healthy aging in humans

Ke Xu, Roman Kosoy, Khader Shameer, Sudhir Kumar, Li Liu, Benjamin Readhead, Gillian M. Belbin, Hao Chih Lee, Rong Chen, Joel T. Dudley

Research output: Contribution to journalArticle

Abstract

Background: Genetic diversity is known to confer survival advantage in many species across the tree of life. 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. Results: We use healthy aging as a proxy for better health and fitness, and observe greater heterozygosity in healthy-aged individuals. Specifically, we find that only common genetic variants show significantly higher excess of heterozygosity in the healthy-aged cohort. 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. 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. 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. Conclusions: 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. Further characterization of this relationship will have important implications in aging-associated disease risk prediction.

Original languageEnglish (US)
Article number52
JournalBMC Genetics
Volume20
Issue number1
DOIs
StatePublished - Jul 2 2019

Fingerprint

Genome-Wide Association Study
Heterozygote
Survival
Electronic Health Records
Age Factors
Proxy
Genes
Single Nucleotide Polymorphism
Extracellular Matrix
Glycoproteins
Alleles
Health

Keywords

  • Balancing selection
  • Electronic health record
  • Fitness
  • Healthy aging
  • Heterozygote advantage
  • Human diseases

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Genome-wide analysis indicates association between heterozygote advantage and healthy aging in humans. / Xu, Ke; Kosoy, Roman; Shameer, Khader; Kumar, Sudhir; Liu, Li; Readhead, Benjamin; Belbin, Gillian M.; Lee, Hao Chih; Chen, Rong; Dudley, Joel T.

In: BMC Genetics, Vol. 20, No. 1, 52, 02.07.2019.

Research output: Contribution to journalArticle

Xu, Ke ; Kosoy, Roman ; Shameer, Khader ; Kumar, Sudhir ; Liu, Li ; Readhead, Benjamin ; Belbin, Gillian M. ; Lee, Hao Chih ; Chen, Rong ; Dudley, Joel T. / Genome-wide analysis indicates association between heterozygote advantage and healthy aging in humans. In: BMC Genetics. 2019 ; Vol. 20, No. 1.
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