Genome-wide association analysis identifies APOE as a mitophagy modifier in Lewy body disease.

ABSTRACT:

Introduction

Phosphorylated ubiquitin (p-S65-Ub) is generated during PINK1-PRKN mitophagy as a specific marker of mitochondrial damage. Despite the widespread deposition of p-S65-Ub in aged and diseased human brain, the genetic contribution to its accumulation remains unclear.

Methods

To identify novel mitophagy regulators, we performed a genome-wide association study using p-S65-Ub level as a quantitative trait in 1012 autopsy-confirmed Lewy body disease (LBD) samples.

Results

We identified a significant genome-wide association with p-S65-Ub for rs429358 (apolipoprotein E ε4 [APOE4]) and a suggestive association for rs6480922 (ZMIZ1). APOE4 was associated with higher p-S65-Ub levels and greater neuropathological burden. Functional validation in mouse and human induce

SUBMITTER: Hou X 

PROVIDER: S-EPMC12044520 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature