Repeat variations in polyglutamine disease-associated genes and cognitive function in old age.

Area of Science:

• Genetics
• Neuroscience
• Aging Research

Background:

• Cognitive function in old age has substantial heritability, but genome-wide association studies (GWAS) have identified limited genetic factors, leaving a
• missing heritability.
• GWAS primarily assess single nucleotide polymorphisms and cannot evaluate other significant genetic variations like tandem repeat polymorphisms.

Purpose of the Study:

• To investigate the association between cytosine-adenine-guanine (CAG) repeat variations in polyglutamine disease-associated genes (PDAGs) and cognitive function in older adults.
• To explore the contribution of these repeat variations to the "missing heritability" of cognitive aging.

Main Methods:

• Analysis of CAG repeat numbers in PDAGs within a large cohort (n=5786) of older adults.
• Correlation of repeat numbers with cognitive function decline.
• Magnetic resonance imaging (MRI) substudy to examine associations between CAG repeat polymorphisms and brain imaging characteristics.

Main Results:

• CAG repeat numbers in three PDAGs (TBP, HTT, AR) were significantly associated with cognitive function decline, explaining 0.49% of the variation.
• CAG repeat polymorphisms in four PDAGs (ATXN2, CACNA1A, ATXN7, AR) were linked to variations in brain volumes (brain stem, putamen, globus pallidus, thalamus, amygdala).

Conclusions:

• Tandem repeat polymorphisms, specifically CAG repeats in PDAGs, are associated with cognitive function and brain structure in older adults.
• These findings suggest that PDAGs and their repeat variations are important contributors to the missing heritability of cognitive aging.