Journal Article

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

Watzlawik, Jens O., Dickson, Dennis W., White, Launia J., Heckman, Michael G., Quicksall, Zachary S., Johnson, Patrick W., Reddy, Joseph S., Springer, Wolfdieter, Zhao, Na, Ross, Owen A., Bras, Jose, Hou, Xu, Soto‐Beasley, Alexandra I., Guerreiro, Rita, Koga, Shunsuke, Valentino, Rebecca R., Bu, Guojun, Zhao, Jing, Fiesel, Fabienne C.

2025

Overview

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 induced pluripotent stem cell (iPSC) models confirmed APOE4‐mediated mitophagy alterations. Intriguingly, ZMIZ1 rs6480922 was associated with lower p‐S65‐Ub levels, reduced neuropathological load, and increased brain weight, indicating a potential protective role. DISCUSSION Our findings underscore the importance of mitochondrial quality control in LBD pathogenesis and nominate regulators that may contribute to disease risk or resilience. Highlights p‐S65‐Ub levels were used as a quantitative marker of mitochondrial damage. A GWAS identified two genetic variants that modify mitophagy in LBD autopsy brain. APOE4 was associated with increased p‐S65‐Ub accumulation and neuropathology. APOE4 altered mitophagy via pathology‐dependent and pathology‐independent mechanisms. ZMIZ1 was linked to reduced p‐S65‐Ub and neuropathology indicative of protection.

• Publisher: John Wiley and Sons Inc
• Subject: Aged / Aged, 80 and over / Animals / Apolipoprotein E4 - genetics / Apolipoproteins E - genetics / autophagy / Brain - metabolism / Brain - pathology / Female / Genome-Wide Association Study / GWAS / Humans / Induced Pluripotent Stem Cells / Lewy Body Disease - genetics / Lewy Body Disease - metabolism / Lewy Body Disease - pathology / Male / Mice / mitochondria / Mitochondria - metabolism / Mitophagy - genetics / Parkin / Parkinson's disease / phosphorylated ubiquitin / PINK1 / Polymorphism, Single Nucleotide / PRKN / ubiquitin / Ubiquitin - metabolism / ZMIZ1