A meta-analysis of genome-wide association studies of epigenetic age acceleration

Jude Gibson; Tom C. Russ; Toni-Kim Clarke; David M. Howard; Robert F. Hillary; Kathryn L. Evans; Rosie M. Walker; Mairead L. Bermingham; Stewart W. Morris; Archie Campbell; Caroline Hayward; Alison D. Murray; David J. Porteous; Steve Horvath; Ake T. Lu; Andrew M. McIntosh; Heather C. Whalley; Riccardo E. Marioni

doi:10.1371/journal.pgen.1008104

A meta-analysis of genome-wide association studies of epigenetic age acceleration

Jude Gibson, Tom C. Russ, Toni-Kim Clarke, David M. Howard, Robert F. Hillary, Kathryn L. Evans, Rosie M. Walker, Mairead L. Bermingham, Stewart W. Morris, Archie Campbell, Caroline Hayward, Alison D. Murray, David J. Porteous, Steve Horvath, Ake T. Lu, Andrew M. McIntosh, Heather C. Whalley, Riccardo E. Marioni^* (Corresponding Author)

^*Corresponding author for this work

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

66 Citations (Scopus)

5 Downloads (Pure)

Abstract

Author summary DNA methylation, an epigenetic process, is known to vary with age. Methylation levels at specific sites across the genome can be combined to form estimates of age known as ‘epigenetic age’. The difference between epigenetic age and chronological age is referred to as ‘epigenetic age acceleration’, with positive values indicating that a person is biologically older than their years. Understanding why some people seem to age faster than others could shed light on the biological processes behind age-related decline; however, the mechanisms underlying differential rates of epigenetic ageing are largely unknown. Here, we investigate genetic determinants of two commonly used epigenetic age acceleration measures, based on the Horvath and Hannum epigenetic clocks. We report novel genetic variants and genes associated with epigenetic age acceleration, and highlight differences in the genetic factors influencing these two measures. We identify ten genetic variants and 21 genes associated with Horvath-based epigenetic age acceleration, and one variant and 12 genes associated with the Hannum-based measure. There were no genome-wide significant variants or genes in common between the Horvath-based and Hannum-based measures, supporting the hypothesis that they represent different aspects of ageing. Our results suggest a partial genetic basis underlying some previously reported phenotypic associations.

Original language	English
Article number	e1008104
Number of pages	30
Journal	PLoS Genetics
Volume	15
Issue number	11
Early online date	18 Nov 2019
DOIs	https://doi.org/10.1371/journal.pgen.1008104
Publication status	Published - Nov 2019

Bibliographical note

Funding: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping and DNA methylation profiling of the GS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” ((STRADL) Reference 104036/Z/14/Z)). Funding details for the cohorts included in the study by Lu et al. (2018) can be found in their publication. HCW is supported by a JMAS SIM fellowship from the Royal College of Physicians of Edinburgh and by an ESAT College Fellowship from the University of Edinburgh. AMM & HCW acknowledge the support of the Dr. Mortimer and Theresa Sackler Foundation. SH acknowledges support from grant 1U01AG060908-01. REM is supported by Alzheimer’s Research UK major project grant ARUK-PG2017B-10. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Data Availability: Summary statistics from the research reported in the manuscript will be made available immediately following publication on the Edinburgh Data Share portal with a permanent digital object identifier (DOI). According to the terms of consent for Generation Scotland participants, requests for access to the individual-level data must be reviewed by the GS Access Committee (resources@generationscotland.org). Individual-level data are not immediately available, due to confidentiality considerations and our legal obligation to protect personal information. These data will, however, be made available upon request and after review by the GS access committee, once ethical and data governance concerns regarding personal data have been addressed by the receiving institution through a Data Transfer Agreement.

Keywords

DNA methylation
ageing
sexual dimorphism
X-chromosome
Generation Scotland

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1371/journal.pgen.1008104Licence: CC BY

Gibson_etal_pgen_1008104_VOR
Copyright: © 2019 Gibson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. https://creativecommons.org/licenses/by/4.0/
Final published version, 2.01 MBLicence: CC BY

Cite this

Gibson, J., Russ, T. C., Clarke, T.-K., Howard, D. M., Hillary, R. F., Evans, K. L., Walker, R. M., Bermingham, M. L., Morris, S. W., Campbell, A., Hayward, C., Murray, A. D., Porteous, D. J., Horvath, S., Lu, A. T., McIntosh, A. M., Whalley, H. C., & Marioni, R. E. (2019). A meta-analysis of genome-wide association studies of epigenetic age acceleration. PLoS Genetics, 15(11), Article e1008104. https://doi.org/10.1371/journal.pgen.1008104

Gibson, J, Russ, TC, Clarke, T-K, Howard, DM, Hillary, RF, Evans, KL, Walker, RM, Bermingham, ML, Morris, SW, Campbell, A, Hayward, C, Murray, AD, Porteous, DJ, Horvath, S, Lu, AT, McIntosh, AM, Whalley, HC & Marioni, RE 2019, 'A meta-analysis of genome-wide association studies of epigenetic age acceleration', PLoS Genetics, vol. 15, no. 11, e1008104. https://doi.org/10.1371/journal.pgen.1008104

@article{4db26fb563624e808eac31ca3ad17bec,

title = "A meta-analysis of genome-wide association studies of epigenetic age acceleration",

abstract = "Author summary DNA methylation, an epigenetic process, is known to vary with age. Methylation levels at specific sites across the genome can be combined to form estimates of age known as {\textquoteleft}epigenetic age{\textquoteright}. The difference between epigenetic age and chronological age is referred to as {\textquoteleft}epigenetic age acceleration{\textquoteright}, with positive values indicating that a person is biologically older than their years. Understanding why some people seem to age faster than others could shed light on the biological processes behind age-related decline; however, the mechanisms underlying differential rates of epigenetic ageing are largely unknown. Here, we investigate genetic determinants of two commonly used epigenetic age acceleration measures, based on the Horvath and Hannum epigenetic clocks. We report novel genetic variants and genes associated with epigenetic age acceleration, and highlight differences in the genetic factors influencing these two measures. We identify ten genetic variants and 21 genes associated with Horvath-based epigenetic age acceleration, and one variant and 12 genes associated with the Hannum-based measure. There were no genome-wide significant variants or genes in common between the Horvath-based and Hannum-based measures, supporting the hypothesis that they represent different aspects of ageing. Our results suggest a partial genetic basis underlying some previously reported phenotypic associations.",

keywords = "DNA methylation, ageing, sexual dimorphism, X-chromosome, Generation Scotland",

author = "Jude Gibson and Russ, {Tom C.} and Toni-Kim Clarke and Howard, {David M.} and Hillary, {Robert F.} and Evans, {Kathryn L.} and Walker, {Rosie M.} and Bermingham, {Mairead L.} and Morris, {Stewart W.} and Archie Campbell and Caroline Hayward and Murray, {Alison D.} and Porteous, {David J.} and Steve Horvath and Lu, {Ake T.} and McIntosh, {Andrew M.} and Whalley, {Heather C.} and Marioni, {Riccardo E.}",

note = "Funding: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping and DNA methylation profiling of the GS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” ((STRADL) Reference 104036/Z/14/Z)). Funding details for the cohorts included in the study by Lu et al. (2018) can be found in their publication. HCW is supported by a JMAS SIM fellowship from the Royal College of Physicians of Edinburgh and by an ESAT College Fellowship from the University of Edinburgh. AMM & HCW acknowledge the support of the Dr. Mortimer and Theresa Sackler Foundation. SH acknowledges support from grant 1U01AG060908-01. REM is supported by Alzheimer{\textquoteright}s Research UK major project grant ARUK-PG2017B-10. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability: Summary statistics from the research reported in the manuscript will be made available immediately following publication on the Edinburgh Data Share portal with a permanent digital object identifier (DOI). According to the terms of consent for Generation Scotland participants, requests for access to the individual-level data must be reviewed by the GS Access Committee (resources@generationscotland.org). Individual-level data are not immediately available, due to confidentiality considerations and our legal obligation to protect personal information. These data will, however, be made available upon request and after review by the GS access committee, once ethical and data governance concerns regarding personal data have been addressed by the receiving institution through a Data Transfer Agreement.",

year = "2019",

month = nov,

doi = "10.1371/journal.pgen.1008104",

language = "English",

volume = "15",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "11",

}

TY - JOUR

T1 - A meta-analysis of genome-wide association studies of epigenetic age acceleration

AU - Gibson, Jude

AU - Russ, Tom C.

AU - Clarke, Toni-Kim

AU - Howard, David M.

AU - Hillary, Robert F.

AU - Evans, Kathryn L.

AU - Walker, Rosie M.

AU - Bermingham, Mairead L.

AU - Morris, Stewart W.

AU - Campbell, Archie

AU - Hayward, Caroline

AU - Murray, Alison D.

AU - Porteous, David J.

AU - Horvath, Steve

AU - Lu, Ake T.

AU - McIntosh, Andrew M.

AU - Whalley, Heather C.

AU - Marioni, Riccardo E.

N1 - Funding: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates (CZD/16/6) and the Scottish Funding Council (HR03006). Genotyping and DNA methylation profiling of the GS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” ((STRADL) Reference 104036/Z/14/Z)). Funding details for the cohorts included in the study by Lu et al. (2018) can be found in their publication. HCW is supported by a JMAS SIM fellowship from the Royal College of Physicians of Edinburgh and by an ESAT College Fellowship from the University of Edinburgh. AMM & HCW acknowledge the support of the Dr. Mortimer and Theresa Sackler Foundation. SH acknowledges support from grant 1U01AG060908-01. REM is supported by Alzheimer’s Research UK major project grant ARUK-PG2017B-10. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data Availability: Summary statistics from the research reported in the manuscript will be made available immediately following publication on the Edinburgh Data Share portal with a permanent digital object identifier (DOI). According to the terms of consent for Generation Scotland participants, requests for access to the individual-level data must be reviewed by the GS Access Committee (resources@generationscotland.org). Individual-level data are not immediately available, due to confidentiality considerations and our legal obligation to protect personal information. These data will, however, be made available upon request and after review by the GS access committee, once ethical and data governance concerns regarding personal data have been addressed by the receiving institution through a Data Transfer Agreement.

PY - 2019/11

Y1 - 2019/11

N2 - Author summary DNA methylation, an epigenetic process, is known to vary with age. Methylation levels at specific sites across the genome can be combined to form estimates of age known as ‘epigenetic age’. The difference between epigenetic age and chronological age is referred to as ‘epigenetic age acceleration’, with positive values indicating that a person is biologically older than their years. Understanding why some people seem to age faster than others could shed light on the biological processes behind age-related decline; however, the mechanisms underlying differential rates of epigenetic ageing are largely unknown. Here, we investigate genetic determinants of two commonly used epigenetic age acceleration measures, based on the Horvath and Hannum epigenetic clocks. We report novel genetic variants and genes associated with epigenetic age acceleration, and highlight differences in the genetic factors influencing these two measures. We identify ten genetic variants and 21 genes associated with Horvath-based epigenetic age acceleration, and one variant and 12 genes associated with the Hannum-based measure. There were no genome-wide significant variants or genes in common between the Horvath-based and Hannum-based measures, supporting the hypothesis that they represent different aspects of ageing. Our results suggest a partial genetic basis underlying some previously reported phenotypic associations.

AB - Author summary DNA methylation, an epigenetic process, is known to vary with age. Methylation levels at specific sites across the genome can be combined to form estimates of age known as ‘epigenetic age’. The difference between epigenetic age and chronological age is referred to as ‘epigenetic age acceleration’, with positive values indicating that a person is biologically older than their years. Understanding why some people seem to age faster than others could shed light on the biological processes behind age-related decline; however, the mechanisms underlying differential rates of epigenetic ageing are largely unknown. Here, we investigate genetic determinants of two commonly used epigenetic age acceleration measures, based on the Horvath and Hannum epigenetic clocks. We report novel genetic variants and genes associated with epigenetic age acceleration, and highlight differences in the genetic factors influencing these two measures. We identify ten genetic variants and 21 genes associated with Horvath-based epigenetic age acceleration, and one variant and 12 genes associated with the Hannum-based measure. There were no genome-wide significant variants or genes in common between the Horvath-based and Hannum-based measures, supporting the hypothesis that they represent different aspects of ageing. Our results suggest a partial genetic basis underlying some previously reported phenotypic associations.

KW - DNA methylation

KW - ageing

KW - sexual dimorphism

KW - X-chromosome

KW - Generation Scotland

UR - http://www.scopus.com/inward/record.url?scp=85076045038&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1008104

DO - 10.1371/journal.pgen.1008104

M3 - Article

C2 - 31738745

SN - 1553-7390

VL - 15

JO - PLoS Genetics

JF - PLoS Genetics

IS - 11

M1 - e1008104

ER -

A meta-analysis of genome-wide association studies of epigenetic age acceleration

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this