Epigenetic Clock Acceleration Is Linked to Age at Onset of Parkinson's Disease

Xuelin Tang; Paulina Gonzalez-Latapi; Connie Marras; Naomi P Visanji; Wanli Yang; Christine Sato; Anthony E Lang; Ekaterina Rogaeva; Ming Zhang

doi:10.1002/mds.29157

Epigenetic Clock Acceleration Is Linked to Age at Onset of Parkinson's Disease

Mov Disord. 2022 Sep;37(9):1831-1840. doi: 10.1002/mds.29157. Epub 2022 Aug 3.

Authors

Xuelin Tang¹, Paulina Gonzalez-Latapi^{2

3}, Connie Marras^{2

4}, Naomi P Visanji^{2

5

6

7}, Wanli Yang¹, Christine Sato⁵, Anthony E Lang^{2

4

7}, Ekaterina Rogaeva^{4

5}, Ming Zhang^{1

8

9}

Affiliations

¹ The First Rehabilitation Hospital of Shanghai, Department of Medical Genetics, School of Medicine, Tongji University, Shanghai, China.
² Edmond J. Safra Program in Parkinson's Disease and Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada.
³ Ken and Ruth Davee Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
⁴ Division of Neurology, University of Toronto, Toronto, Ontario, Canada.
⁵ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada.
⁶ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
⁷ Krembil Brain Institute, Toronto, Ontario, Canada.
⁸ Clinical Center for Brain and Spinal Cord Research, Tongji University, Shanghai, China.
⁹ Institute for Advanced Study, Tongji University, Shanghai, China.

PMID: 35921480
DOI: 10.1002/mds.29157

Abstract

Background: Aging is the strongest risk factor for Parkinson's disease (PD), which is a clinically heterogeneous movement disorder with highly variable age at onset. DNA methylation age (DNAm age) is an epigenetic clock that could reflect biological aging.

Objectives: The aim was to evaluate whether PD age at onset is associated with DNAm-age acceleration (difference between DNAm age and chronological age).

Methods: We used the genome-wide Infinium MethylationEPIC array to assess DNAm age in discovery (n = 96) and replication (n = 182) idiopathic PD cohorts and a unique longitudinal LRRK2 cohort (n = 220) at four time points over a 3-year period, comprising 91 manifesting and 129 nonmanifesting G2019S carriers at baseline. Cox proportional hazard regression and multivariate linear regression were used to evaluate the relation between DNAm-age acceleration and PD age at onset, which was highly variable in manifesting G2019S carriers (36-75 years) and both idiopathic PD cohorts (26-77 and 35-81 years).

Results: DNAm-age acceleration remained steady over the 3-year period in most G2019S carriers. It was strongly associated with age at onset in the LRRK2 cohort (P = 2.25 × 10^-15 ) and discovery idiopathic PD cohort (P = 5.39 × 10^-9 ), suggesting that every 5-year increase in DNAm-age acceleration is related to about a 6-year earlier onset. This link was replicated in an independent idiopathic PD cohort (P = 1.91 × 10^-10 ). In each cohort, the faster-aging group has an increased hazard for an earlier onset (up to 255%).

Conclusions: This study is the first to demonstrate that DNAm-age acceleration is related to PD age at onset, which could be considered in disease-modifying clinical trials. Future studies should evaluate the stability of DNAm-age acceleration over longer time periods, especially for phenoconverters from nonmanifesting to manifesting individuals. © 2022 International Parkinson and Movement Disorder Society.

Keywords: DNA methylation; LRRK2 mutation; Parkinson's disease; epigenetic clock.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acceleration
Adult
Age of Onset
Aged
Epigenesis, Genetic
Epigenomics
Humans
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics
Middle Aged
Mutation / genetics
Parkinson Disease* / epidemiology
Parkinson Disease* / genetics

Substances

Leucine-Rich Repeat Serine-Threonine Protein Kinase-2