Loss of function and structural variants in the PRKRA synaptic gene link mild cognitive impairment and tinnitus

The genetic basis underlying the co-occurrence of tinnitus and mild cognitive impairment (MCI) remains unknown. Adults with chronic tinnitus from a European cohort were classified into MCI (n=75) and non-MCI (n=201) groups, and rare variant distributions were assessed using gene burden analyses. Approximately one-fourth of individuals with chronic tinnitus exhibited MCI in their early fifties. Rare loss-of-function variants in PRKRA were identified in 18.6% of MCI patients, including a recurrent [~]3kb deletion in 14 individuals (OR=513.86, 95% CI [224.34-1177.02], adjusted p-value = 1.04E-48). These carriers reported tinnitus onset approximately eight years before MCI was observed. Cognitive impairment was linked to tinnitus, but not to hyperacusis or high-frequency hearing loss, among carriers of rare variants in MCI candidate genes, particularly PRKRA. The association between PRKRA variants and MCI was independent of APOE {varepsilon}4 allele and known Parkinsons disease dementia risk variants. In silico modelling and docking show increased binding affinity between mutant PACT (PRKRA) and PKR, suggesting over-activation of the PKR-eIF2 integrated stress response. Functional validation using a PRKRA knockout model identified differentially expressed genes enriched in dementia-related pathways. These findings support PRKRA as a potential driver gene in tinnitus-associated MCI. Clinicaltrial.gov: NCT04663828