Tissue-specific impacts of aging and genetics on gene expression patterns in humans

• DOI: 10.1038/s41467-022-33509-0
• Publication Date: 2022-10-03T07:02:58Z
• Authors: Ryo Yamamoto; Ryan Chung; Juan Manuel Vazquez; Huanjie Sheng; Philippa L. Stein...; Nilah M. Ioannidis; Peter H. Sudmant
• Keywords: 0301 basic medicine; 570; Aging; Science; Human Genome; Q; Quantitative Trait Loci; 610; Gene Expression; Article; 3. Good health; 03 medical and health sciences; Phenotype; Gene Expression Regulation; Genetics; 2.1 Biological and endogenous factors; Humans; Genetic Testing; Generic health relevance; Aetiology; Biotechnology

AbstractAge is the primary risk factor for many common human diseases. Here, we quantify the relative contributions of genetics and aging to gene expression patterns across 27 tissues from 948 humans. We show that the predictive power of expression quantitative trait loci is impacted by age in many tissues. Jointly modelling the contributions of age and genetics to transcript level variation we find expression heritability (h2) is consistent among tissues while the contribution of aging varies by >20-fold with $${R}_{{{{{{{{\rm{age}}}}}}}}}^{2} \; > \;{h}^{2}$$

R

age

2

>

h

2

in 5 tissues. We find that while the force of purifying selection is stronger on genes expressed early versus late in life (Medawar’s hypothesis), several highly proliferative tissues exhibit the opposite pattern. These non-Medawarian tissues exhibit high rates of cancer and age-of-expression-associated somatic mutations. In contrast, genes under genetic control are under relaxed constraint. Together, we demonstrate the distinct roles of aging and genetics on expression phenotypes.