Epigenetic Clock Acceleration Is Linked to Age at Onset of Parkinson's Disease
© 2022 International Parkinson and Movement Disorder Society..
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.
| Errataetall: |
CommentIn: Nat Rev Neurol. 2022 Oct;18(10):575. - PMID 36071269 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:37 |
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| Enthalten in: |
Movement disorders : official journal of the Movement Disorder Society - 37(2022), 9 vom: 19. Sept., Seite 1831-1840 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Tang, Xuelin [VerfasserIn] |
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| Links: |
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| Themen: |
DNA methylation |
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| Anmerkungen: |
Date Completed 15.09.2022 Date Revised 11.10.2022 published: Print-Electronic CommentIn: Nat Rev Neurol. 2022 Oct;18(10):575. - PMID 36071269 Citation Status MEDLINE |
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| doi: |
10.1002/mds.29157 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM344410544 |
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| 245 | 1 | 0 | |a Epigenetic Clock Acceleration Is Linked to Age at Onset of Parkinson's Disease |
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| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Nat Rev Neurol. 2022 Oct;18(10):575. - PMID 36071269 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2022 International Parkinson and Movement Disorder Society. | ||
| 520 | |a 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 | ||
| 520 | |a OBJECTIVES: The aim was to evaluate whether PD age at onset is associated with DNAm-age acceleration (difference between DNAm age and chronological age) | ||
| 520 | |a 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) | ||
| 520 | |a 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%) | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a LRRK2 mutation | |
| 650 | 4 | |a Parkinson's disease | |
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| 700 | 1 | |a Gonzalez-Latapi, Paulina |e verfasserin |4 aut | |
| 700 | 1 | |a Marras, Connie |e verfasserin |4 aut | |
| 700 | 1 | |a Visanji, Naomi P |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Wanli |e verfasserin |4 aut | |
| 700 | 1 | |a Sato, Christine |e verfasserin |4 aut | |
| 700 | 1 | |a Lang, Anthony E |e verfasserin |4 aut | |
| 700 | 1 | |a Rogaeva, Ekaterina |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ming |e verfasserin |4 aut | |
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