# Job-related exhaustion risk variant in UST is associated with dementia and DNA methylation

## TL;DR

A genetic variant linked to job-related exhaustion is also associated with increased dementia risk and changes in DNA methylation.

## Contribution

The study identifies a genetic variant in UST that connects stress-related exhaustion with dementia and DNA methylation.

## Key findings

- The AA genotype of rs13219957 is linked to a 40% higher risk of all-cause dementia.
- The UST variant is associated with tau pathology but not amyloid pathology in the brain.
- rs13219957 is strongly linked to DNA methylation and UST gene expression.

## Abstract

Previous genome-wide association and replication study for job-related exhaustion indicated a risk variant, rs13219957 in the UST gene. Epidemiological studies suggest connection of stress-related conditions and dementia risk. Therefore, we first studied association of rs13219957 and register-based incident dementia using survival models in the Finnish National FINRISK study surveys (N = 26,693). The AA genotype of rs13219957 was significantly associated with 40% increased risk of all-cause dementia. Then we analysed the UST locus association with brain pathology in the Vantaa 85+ cohort and found association with tau pathology (Braak stage) but not with amyloid pathology. Finally, in the functional analyses, rs13219957 showed a highly significant association with two DNA methylation sites of UST, and UST expression. Thus, the results suggest a common risk variant for a stress-related condition and dementia. Mechanisms to mediate the connection may include differential DNA methylation and transcriptional regulation of UST.