Objective:

To investigate the frequency of Alzheimer's disease and related dementias (ADRD) or Parkinson’s disease (PD) associated with EPG5 missense mutation.

Background:

EPG5 functions as a mediator of the autophagosome-lysosome fusion pathway. The disruption of this pathway may lead to accumulation of dysfunctional cellular components which may contribute to the development of neurodegenerative diseases.

Design/Methods:

Participants in the All of Us Research Program over the age of 40 with medical records and short-read whole genome sequencing data (n=64,739) were analyzed. The five most common EPG5 missense variants (rs3744998, rs1893523, rs59422275, rs3744999, and rs34064739) were analyzed in conjunction with the presence of diagnosis for one of two neurodegenerative diseases: ADRD and PD. ADRD and PD diagnoses were determined using available Electronic Health Records (EHR) data and EPG5 missense mutation was determined using short-read whole genome sequencing. Odds ratios (OR) were calculated to assess relationship association. Bonferroni-adjusted analyses were performed with p<0.002 considered significant after correction.

Results:

rs3744998 was associated with significantly higher odds of having a PD diagnosis (OR = 1.35, p<10E-6), while rs1893523 and rs34064739 were found to have lower odds of both AD and PD diagnoses (AD OR = 0.75, PD OR = 0.58; AD OR = 0.51, PD OR = 0.31, p<0.001). In men, rs3744998 was associated with significantly higher odds of PD diagnosis (OR = 1.38, p<0.001) and rs1893523 was associated with significantly decreased odds of AD diagnosis (OR = 0.62, p<0.001) compared to in women. rs1893523 was associated with significantly decreased odds of PD diagnosis regardless of sex (OR= 0.59 in men, 0.67 in women, p<0.001).

Conclusions:

These data suggest several genetic variants in EPG5 may influence the development of neurodegenerative diseases.