Epigenome-wide analyses identify DNA methylation signatures of dementia risk

Rosie Walker; Mairead Bermingham; Kadi Vaher; Stewart Morris; Toni Clarke; Andrew D Bretherick; Yanni Zeng; Carmen Amador; Konrad Rawlik; Kalyani Pandya; Caroline Hayward; Archie Campbell; David John Porteous; Andrew McIntosh; Riccardo E Marioni; Kathryn Louise Evans

doi:10.1002/dad2.12078

Epigenome-wide analyses identify DNA methylation signatures of dementia risk

Rosie Walker, Mairead Bermingham, Kadi Vaher, Stewart Morris, Toni Clarke, Andrew D Bretherick, Yanni Zeng, Carmen Amador, Konrad Rawlik, Kalyani Pandya, Caroline Hayward, Archie Campbell, David John Porteous, Andrew McIntosh, Riccardo E Marioni, Kathryn Louise Evans

Research output: Contribution to journal › Article › peer-review

Abstract

Introduction
Dementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimer's disease (AD)–free participants.

Methods
Associations between dementia risk measures (family history, AD genetic risk score [GRS], and dementia risk scores [combining lifestyle, demographic, and genetic factors]) and whole-blood DNA methylation were assessed in discovery and replication samples (n = ~400 to ~5000) from Generation Scotland.

Results
AD genetic risk and two dementia risk scores were associated with differential methylation. The GRS associated predominantly with methylation differences in cis but also identified a genomic region implicated in Parkinson disease. Loci associated with dementia risk scores were enriched for those previously associated with body mass index and alcohol consumption.

Discussion
Dementia risk measures show widespread association with blood-based methylation, generating several hypotheses for assessment by future studies.

Original language	English
Article number	e12078
Journal	Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Volume	12
Issue number	1
Early online date	10 Aug 2020
DOIs	https://doi.org/10.1002/dad2.12078
Publication status	Published - 10 Aug 2020

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10.1002/dad2.12078

OA_DAD2-12-e12078
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Stratifying Resilience and Depression Longitudinally
McIntosh, A., Deary, I., Evans, K., Haley, C. & Porteous, D.
UK-based charities
1/01/15 → 30/06/21
Project: Research

Andrew McIntosh
- Deanery of Clinical Sciences - Chair of Biological Psychiatry
- Centre for Clinical Brain Sciences
- Edinburgh Neuroscience
Person: Academic: Research Active

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Walker, R., Bermingham, M., Vaher, K., Morris, S., Clarke, T., Bretherick, A. D., Zeng, Y., Amador, C., Rawlik, K., Pandya, K., Hayward, C., Campbell, A., Porteous, D. J., McIntosh, A., Marioni, R. E., & Evans, K. L. (2020). Epigenome-wide analyses identify DNA methylation signatures of dementia risk. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, 12(1), Article e12078. https://doi.org/10.1002/dad2.12078

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title = "Epigenome-wide analyses identify DNA methylation signatures of dementia risk",

abstract = "IntroductionDementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimer's disease (AD)–free participants.MethodsAssociations between dementia risk measures (family history, AD genetic risk score [GRS], and dementia risk scores [combining lifestyle, demographic, and genetic factors]) and whole-blood DNA methylation were assessed in discovery and replication samples (n = ~400 to ~5000) from Generation Scotland.ResultsAD genetic risk and two dementia risk scores were associated with differential methylation. The GRS associated predominantly with methylation differences in cis but also identified a genomic region implicated in Parkinson disease. Loci associated with dementia risk scores were enriched for those previously associated with body mass index and alcohol consumption.DiscussionDementia risk measures show widespread association with blood-based methylation, generating several hypotheses for assessment by future studies.",

author = "Rosie Walker and Mairead Bermingham and Kadi Vaher and Stewart Morris and Toni Clarke and Bretherick, {Andrew D} and Yanni Zeng and Carmen Amador and Konrad Rawlik and Kalyani Pandya and Caroline Hayward and Archie Campbell and Porteous, {David John} and Andrew McIntosh and Marioni, {Riccardo E} and Evans, {Kathryn Louise}",

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Walker, R, Bermingham, M, Vaher, K, Morris, S, Clarke, T, Bretherick, AD, Zeng, Y, Amador, C, Rawlik, K, Pandya, K, Hayward, C , Campbell, A, Porteous, DJ, McIntosh, A , Marioni, RE & Evans, KL 2020, 'Epigenome-wide analyses identify DNA methylation signatures of dementia risk', Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring, vol. 12, no. 1, e12078. https://doi.org/10.1002/dad2.12078

TY - JOUR

T1 - Epigenome-wide analyses identify DNA methylation signatures of dementia risk

AU - Walker, Rosie

AU - Bermingham, Mairead

AU - Vaher, Kadi

AU - Morris, Stewart

AU - Clarke, Toni

AU - Bretherick, Andrew D

AU - Zeng, Yanni

AU - Amador, Carmen

AU - Rawlik, Konrad

AU - Pandya, Kalyani

AU - Hayward, Caroline

AU - Campbell, Archie

AU - Porteous, David John

AU - McIntosh, Andrew

AU - Marioni, Riccardo E

AU - Evans, Kathryn Louise

PY - 2020/8/10

Y1 - 2020/8/10

N2 - IntroductionDementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimer's disease (AD)–free participants.MethodsAssociations between dementia risk measures (family history, AD genetic risk score [GRS], and dementia risk scores [combining lifestyle, demographic, and genetic factors]) and whole-blood DNA methylation were assessed in discovery and replication samples (n = ~400 to ~5000) from Generation Scotland.ResultsAD genetic risk and two dementia risk scores were associated with differential methylation. The GRS associated predominantly with methylation differences in cis but also identified a genomic region implicated in Parkinson disease. Loci associated with dementia risk scores were enriched for those previously associated with body mass index and alcohol consumption.DiscussionDementia risk measures show widespread association with blood-based methylation, generating several hypotheses for assessment by future studies.

AB - IntroductionDementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimer's disease (AD)–free participants.MethodsAssociations between dementia risk measures (family history, AD genetic risk score [GRS], and dementia risk scores [combining lifestyle, demographic, and genetic factors]) and whole-blood DNA methylation were assessed in discovery and replication samples (n = ~400 to ~5000) from Generation Scotland.ResultsAD genetic risk and two dementia risk scores were associated with differential methylation. The GRS associated predominantly with methylation differences in cis but also identified a genomic region implicated in Parkinson disease. Loci associated with dementia risk scores were enriched for those previously associated with body mass index and alcohol consumption.DiscussionDementia risk measures show widespread association with blood-based methylation, generating several hypotheses for assessment by future studies.

U2 - 10.1002/dad2.12078

DO - 10.1002/dad2.12078

M3 - Article

SN - 2352-8729

VL - 12

JO - Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

JF - Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring

IS - 1

M1 - e12078

ER -

Epigenome-wide analyses identify DNA methylation signatures of dementia risk

Abstract

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