Genome-wide Survival Study Identifies PARL as a Novel Locus for Clinical Progression and Neurodegeneration in Alzheimer's Disease

Shi-Dong Chen; Wei Zhang; Yi-Wei Feng; Bang-Sheng Wu; Liu Yang; Ya-Ru Zhang; Hui-Fu Wang; Yu Guo; Yue-Ting Deng; Jian-Feng Feng; Wei Cheng; Qiang Dong; Jin-Tai Yu

doi:10.1016/j.biopsych.2023.02.992

Genome-wide Survival Study Identifies PARL as a Novel Locus for Clinical Progression and Neurodegeneration in Alzheimer's Disease

Biol Psychiatry. 2023 Nov 1;94(9):732-742. doi: 10.1016/j.biopsych.2023.02.992. Epub 2023 Mar 3.

Authors

Shi-Dong Chen¹, Wei Zhang², Yi-Wei Feng¹, Bang-Sheng Wu¹, Liu Yang¹, Ya-Ru Zhang¹, Hui-Fu Wang², Yu Guo¹, Yue-Ting Deng¹, Jian-Feng Feng³, Wei Cheng⁴, Qiang Dong⁵, Jin-Tai Yu⁶

Affiliations

¹ Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, National Center for Neurological Disorders, Shanghai, China.
² Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, Shanghai, China.
³ Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, Shanghai, China; Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China; Fudan ISTBI-ZJNU Algorithm Centre for Brain-Inspired Intelligence, Zhejiang Normal University, Jinhua, China; MOE Frontiers Center for Brain Science, Fudan University, Shanghai, Shanghai, China; Zhangjiang Fudan International Innovation Center, Shanghai, China.
⁴ Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, National Center for Neurological Disorders, Shanghai, China; Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, Shanghai, China; Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China; Fudan ISTBI-ZJNU Algorithm Centre for Brain-Inspired Intelligence, Zhejiang Normal University, Jinhua, China.
⁵ Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, National Center for Neurological Disorders, Shanghai, China. Electronic address: dong_qiang@fudan.edu.cn.
⁶ Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, National Center for Neurological Disorders, Shanghai, China. Electronic address: jintai_yu@fudan.edu.cn.

PMID: 36870520
DOI: 10.1016/j.biopsych.2023.02.992

Abstract

Background: Variability exists in the trajectories of Alzheimer's disease (AD). We aimed to identify genetic modulators of clinical progression in AD.

Methods: We conducted the first genome-wide survival study on AD using a two-stage approach. The discovery and replication stage separately included 1158 and 211,817 individuals without dementia from the Alzheimer's Disease Neuroimaging Initiative and the UK Biobank, respectively (325 and 1103 progressed in average follow-up of 4.33 and 8.63 years, respectively). Cox proportional hazards models were applied with time to AD dementia as the phenotype of clinical progression. A series of bioinformatic analyses and functional experiments was performed to validate the novel findings.

Results: We found that APOE and PARL, a novel locus tagged by rs6795172 (hazard ratio = 1.66, p = 1.45 × 10^-9), were significantly associated with AD clinical progression and were successfully replicated. The novel locus was linked to accelerated cognitive changes, higher tau levels, and faster atrophy of AD-specific brain structures, which were also verified in UK Biobank neuroimaging follow-up. Gene analysis and summary data-based Mendelian randomization indicated PARL as the most functionally relevant gene in the locus. Expression quantitative trait locus analyses and dual-luciferase reporter assays confirmed that PARL expression could be regulated by rs6795172. Three different AD mouse models consistently showed decreased PARL expression accompanied by elevated tau levels, and in vitro experiments revealed that knockdown/overexpression of PARL inversely changed tau levels.

Conclusions: Collectively, genetic, bioinformatic, and functional evidence suggests that PARL modulates clinical progression and neurodegeneration in AD. Targeting PARL may potentially modify AD progression and have implications for disease-modifying therapies.

Keywords: Alzheimer’s disease; Clinical progression; Genome-wide survival study; Neurodegeneration; PARL.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Alzheimer Disease* / diagnostic imaging
Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Animals
Biomarkers
Brain
Disease Progression
Mice
Neuroimaging
tau Proteins / genetics
tau Proteins / metabolism

Substances

Biomarkers
tau Proteins
Amyloid beta-Peptides

Grants and funding

U01 AG024904/AG/NIA NIH HHS/United States