Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging...

Area of Science:

• Genetics
• Neuroscience
• Aging Research

Background:

• Human aging exhibits significant individual variability in associated traits like cognitive decline.
• Existing methods lack unbiased quantification of age-associated phenotypic variation within specific tissues.

Purpose of the Study:

• To introduce differential aging (Δ-aging), a novel unbiased method for quantifying individual variability in age-associated phenotypes.
• To apply Δ-aging to human cerebral cortex transcriptome data to identify genetic determinants of brain aging.

Main Methods:

• Development and application of the differential aging (Δ-aging) method.
• Analysis of transcriptome-wide gene expression data from 1,904 human brain samples.
• Genome-wide association study (GWAS) to identify genetic loci associated with Δ-aging.

Main Results:

• Identification of TMEM106B and GRN gene loci as significant determinants of Δ-aging in the cerebral cortex.
• TMEM106B risk variants are linked to inflammation, neuronal loss, and cognitive deficits, independent of diagnosed brain disease.
• The effect of TMEM106B variants is specific to the frontal cerebral cortex in individuals over 65 years old.

Conclusions:

• The differential aging (Δ-aging) method provides a robust framework for analyzing individual aging variability.
• TMEM106B and GRN are key genetic factors influencing cerebral cortex aging and associated cognitive phenotypes.
• The developed methodology can be broadly applied to study aging and other quantitative traits across various biological contexts.