Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

doi:10.1186/s13059-021-02398-9

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

,

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Abstract

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

Original language	English
Article number	194
Journal	Genome Biology
Volume	22
Issue number	1
DOIs	https://doi.org/10.1186/s13059-021-02398-9
State	Published - Dec 2021

Bibliographical note

Funding Information:
REM, SH, and AL are supported by a National Institute of Health U01 grant, U01AG060908–01. REM and DLM are supported by Alzheimer’s Research UK major project grant, ARUK-PG2017B-10. RCR is a de Pass Vice Chancellor’s Research Fellow at the University of Bristol. CR and RCR receive support from a Cancer Research UK Program Grant (C18281/A191169). CLR, JLM, and RCR are members of the UK Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/5). IJD is supported by Age UK (Disconnected Mind program), UKRI Medical Research Council grant, MR/R0245065/1, and by National Institute of Health R01 grant, 1R01AG054628-01A1. GD is supported by the University of Edinburgh School of Philosophy, Psychology and Language Sciences. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Cohort-specific acknowledgements are presented in Additional file .

Publisher Copyright:
© 2021, The Author(s).

Keywords

DNA methylation
Epigenetic clock
GWAS

ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Genetics
Cell Biology

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10.1186/s13059-021-02398-9

Cite this

@article{948b4e678347496eaba540883becb43b,

title = "Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging",

abstract = "Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.",

keywords = "DNA methylation, Epigenetic clock, GWAS",

author = "McCartney, {Daniel L.} and Min, {Josine L.} and Richmond, {Rebecca C.} and Lu, {Ake T.} and Sobczyk, {Maria K.} and Gail Davies and Linda Broer and Xiuqing Guo and Ayoung Jeong and Jeesun Jung and Silva Kasela and Seyma Katrinli and Kuo, {Pei Lun} and Matias-Garcia, {Pamela R.} and Mishra, {Pashupati P.} and Marianne Nygaard and Teemu Palviainen and Amit Patki and Raffield, {Laura M.} and Ratliff, {Scott M.} and Richardson, {Tom G.} and Oliver Robinson and Mette Soerensen and Dianjianyi Sun and Tsai, {Pei Chien} and {van der Zee}, {Matthijs D.} and Walker, {Rosie M.} and Xiaochuan Wang and Yunzhang Wang and Rui Xia and Zongli Xu and Jie Yao and Wei Zhao and Adolfo Correa and Eric Boerwinkle and Dugu{\'e}, {Pierre Antoine} and Peter Durda and Elliott, {Hannah R.} and Christian Gieger and {de Geus}, {Eco J.C.} and Harris, {Sarah E.} and Gibran Hemani and Medea Imboden and Mika K{\"a}h{\"o}nen and Kardia, {Sharon L.R.} and Kresovich, {Jacob K.} and Shengxu Li and Lunetta, {Kathryn L.} and Massimo Mangino and Donna Arnett",

note = "Funding Information: REM, SH, and AL are supported by a National Institute of Health U01 grant, U01AG060908–01. REM and DLM are supported by Alzheimer{\textquoteright}s Research UK major project grant, ARUK-PG2017B-10. RCR is a de Pass Vice Chancellor{\textquoteright}s Research Fellow at the University of Bristol. CR and RCR receive support from a Cancer Research UK Program Grant (C18281/A191169). CLR, JLM, and RCR are members of the UK Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/5). IJD is supported by Age UK (Disconnected Mind program), UKRI Medical Research Council grant, MR/R0245065/1, and by National Institute of Health R01 grant, 1R01AG054628-01A1. GD is supported by the University of Edinburgh School of Philosophy, Psychology and Language Sciences. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Cohort-specific acknowledgements are presented in Additional file . Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

doi = "10.1186/s13059-021-02398-9",

language = "English",

volume = "22",

number = "1",

}

TY - JOUR

T1 - Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

AU - McCartney, Daniel L.

AU - Min, Josine L.

AU - Richmond, Rebecca C.

AU - Lu, Ake T.

AU - Sobczyk, Maria K.

AU - Davies, Gail

AU - Broer, Linda

AU - Guo, Xiuqing

AU - Jeong, Ayoung

AU - Jung, Jeesun

AU - Kasela, Silva

AU - Katrinli, Seyma

AU - Kuo, Pei Lun

AU - Matias-Garcia, Pamela R.

AU - Mishra, Pashupati P.

AU - Nygaard, Marianne

AU - Palviainen, Teemu

AU - Patki, Amit

AU - Raffield, Laura M.

AU - Ratliff, Scott M.

AU - Richardson, Tom G.

AU - Robinson, Oliver

AU - Soerensen, Mette

AU - Sun, Dianjianyi

AU - Tsai, Pei Chien

AU - van der Zee, Matthijs D.

AU - Walker, Rosie M.

AU - Wang, Xiaochuan

AU - Wang, Yunzhang

AU - Xia, Rui

AU - Xu, Zongli

AU - Yao, Jie

AU - Zhao, Wei

AU - Correa, Adolfo

AU - Boerwinkle, Eric

AU - Dugué, Pierre Antoine

AU - Durda, Peter

AU - Elliott, Hannah R.

AU - Gieger, Christian

AU - de Geus, Eco J.C.

AU - Harris, Sarah E.

AU - Hemani, Gibran

AU - Imboden, Medea

AU - Kähönen, Mika

AU - Kardia, Sharon L.R.

AU - Kresovich, Jacob K.

AU - Li, Shengxu

AU - Lunetta, Kathryn L.

AU - Mangino, Massimo

AU - Arnett, Donna

N1 - Funding Information: REM, SH, and AL are supported by a National Institute of Health U01 grant, U01AG060908–01. REM and DLM are supported by Alzheimer’s Research UK major project grant, ARUK-PG2017B-10. RCR is a de Pass Vice Chancellor’s Research Fellow at the University of Bristol. CR and RCR receive support from a Cancer Research UK Program Grant (C18281/A191169). CLR, JLM, and RCR are members of the UK Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/5). IJD is supported by Age UK (Disconnected Mind program), UKRI Medical Research Council grant, MR/R0245065/1, and by National Institute of Health R01 grant, 1R01AG054628-01A1. GD is supported by the University of Edinburgh School of Philosophy, Psychology and Language Sciences. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). Core support including centralized genomic read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1; contract HHSN268201800002I). Core support including phenotype harmonization, data management, sample-identity QC, and general program coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Cohort-specific acknowledgements are presented in Additional file . Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

AB - Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

KW - DNA methylation

KW - Epigenetic clock

KW - GWAS

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U2 - 10.1186/s13059-021-02398-9

DO - 10.1186/s13059-021-02398-9

M3 - Article

C2 - 34187551

AN - SCOPUS:85109008239

VL - 22

IS - 1

M1 - 194

ER -

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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