Integrative analysis of clinical and epigenetic biomarkers of mortality

Tianxiao Huan; Steve Nguyen; Elena Colicino; Carolina Ochoa-Rosales; W. David Hill; Jennifer A. Brody; Mette Soerensen; Yan Zhang; Antoine Baldassari; Mohamed Ahmed Elhadad; Tanaka Toshiko; Yinan Zheng; Arce Domingo-Relloso; Dong Heon Lee; Jiantao Ma; Chen Yao; Chunyu Liu; Shih Jen Hwang; Roby Joehanes; Myriam Fornage; Jan Bressler; Joyce B.J. van Meurs; Birgit Debrabant; Jonas Mengel-From; Jacob Hjelmborg; Kaare Christensen; Pantel Vokonas; Joel Schwartz; Sina A. Gahrib; Nona Sotoodehnia; Colleen M. Sitlani; Sonja Kunze; Christian Gieger; Annette Peters; Melanie Waldenberger; Ian J. Deary; Luigi Ferrucci; Yishu Qu; Philip Greenland; Donald M. Lloyd-Jones; Lifang Hou; Stefania Bandinelli; Trudy Voortman; Brenner Hermann; Andrea Baccarelli; Eric Whitsel; James S. Pankow; Daniel Levy

doi:10.1111/acel.13608

Integrative analysis of clinical and epigenetic biomarkers of mortality

Tianxiao Huan, Steve Nguyen, Elena Colicino, Carolina Ochoa-Rosales, W. David Hill, Jennifer A. Brody, Mette Soerensen, Yan Zhang, Antoine Baldassari, Mohamed Ahmed Elhadad, Tanaka Toshiko, Yinan Zheng, Arce Domingo-Relloso, Dong Heon Lee, Jiantao Ma, Chen Yao, Chunyu Liu, Shih Jen Hwang, Roby Joehanes, Myriam FornageJan Bressler, Joyce B.J. van Meurs, Birgit Debrabant, Jonas Mengel-From, Jacob Hjelmborg, Kaare Christensen, Pantel Vokonas, Joel Schwartz, Sina A. Gahrib, Nona Sotoodehnia, Colleen M. Sitlani, Sonja Kunze, Christian Gieger, Annette Peters, Melanie Waldenberger, Ian J. Deary, Luigi Ferrucci, Yishu Qu, Philip Greenland, Donald M. Lloyd-Jones, Lifang Hou, Stefania Bandinelli, Trudy Voortman, Brenner Hermann, Andrea Baccarelli, Eric Whitsel, James S. Pankow, Daniel Levy

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

4 Scopus citations

Abstract

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10 -7 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, P MR = 4.1 × 10 -4 ) and negatively associated with longevity (Beta = -1.9, P MR = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

Original language	English (US)
Article number	e13608
Journal	Aging cell
Volume	21
Issue number	6
DOIs	https://doi.org/10.1111/acel.13608
State	Published - Jun 2022

Bibliographical note

Funding Information:
The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, National Institutes of Health, Bethesda, MD. The Cardiovascular Health Study is supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, U01HL130114, K08HL116640, R01HL087652, R01HL092111, R01HL103612, R01HL105756, R01HL103612, R01HL111089, R01HL116747 and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA), Merck Foundation/Society of Epidemiologic Research as well as Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. The DTR study was supported by The Danish Council for Independent Research—Medical Sciences (DFF-6110-00016), the European Union's Seventh Framework Programme (FP7/2007–2011) under grant Agreement No. 259679 and The Danish National Program for Research Infrastructure 2007 (09-063256). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Work in WHI was NIEHS-supported by R01-ES020836 (EAW; AB; LH). Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Methylation typing was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. IJD is a member of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE), which is supported by funding from the BBSRC, the Medical Research Council (MRC), and the University of Edinburgh as part of the cross-council Lifelong Health and Wellbeing initiative (MR/K026992/1). W.D.H. is supported by a grant from Age UK (Disconnected Mind Project). The VA Normative Aging Study is sponsored by the CSP/ERIC program of the U.S. Department of Veterans Affairs and is a research component of the Massachusetts Veterans Education Research and Information Center (MAVERIC). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005. Funding was also supported by 5RC2HL102419 and R01NS087541. The authors thank the staff and participants of the ARIC study for their important contributions. J.M. is supported by a grant from NIH HL135075. W.D.H. is supported by a Career Development Award from the Medical Research Council (MRC) [MR/T030852/1] for the project titled “From genetic sequence to phenotypic consequence: genetic and environmental links between cognitive ability, socioeconomic position, and health.” The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. For a list of all the investigators who have contributed to WHI science, please visit: https://s3-us-west-2.amazonaws.com/www-whi-org/wp-content/uploads/WHI-Investigator-Long-List.pdf.

Funding Information:
The Framingham Heart Study is funded by National Institutes of Health contract N01‐HC‐25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, National Institutes of Health, Bethesda, MD. The Cardiovascular Health Study is supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, U01HL130114, K08HL116640, R01HL087652, R01HL092111, R01HL103612, R01HL105756, R01HL103612, R01HL111089, R01HL116747 and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA), Merck Foundation/Society of Epidemiologic Research as well as Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS‐NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. The study was supported by The Danish Council for Independent Research—Medical Sciences (DFF‐6110‐00016), the European Union's Seventh Framework Programme (FP7/2007–2011) under grant Agreement No. 259679 and The Danish National Program for Research Infrastructure 2007 (09‐063256). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Work in WHI was NIEHS‐supported by R01‐ES020836 (EAW; AB; LH). Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Methylation typing was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. IJD is a member of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE), which is supported by funding from the BBSRC, the Medical Research Council (MRC), and the University of Edinburgh as part of the cross‐council Lifelong Health and Wellbeing initiative (MR/K026992/1). W.D.H. is supported by a grant from Age UK (Disconnected Mind Project). The VA Normative Aging Study is sponsored by the CSP/ERIC program of the U.S. Department of Veterans Affairs and is a research component of the Massachusetts Veterans Education Research and Information Center (MAVERIC). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005. Funding was also supported by 5RC2HL102419 and R01NS087541. The authors thank the staff and participants of the ARIC study for their important contributions. J.M. is supported by a grant from NIH HL135075. W.D.H. is supported by a Career Development Award from the Medical Research Council (MRC) [MR/T030852/1] for the project titled “From genetic sequence to phenotypic consequence: genetic and environmental links between cognitive ability, socioeconomic position, and health.” DTR

Publisher Copyright:
© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Keywords

DNA methylation
cancer
cardiovascular disease
machine learning
mortality
Cardiovascular Diseases/genetics
Epigenomics
Epigenesis, Genetic
Humans
DNA Methylation/genetics
Male
Neoplasms/genetics
Biomarkers

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Meta-Analysis
Journal Article
Research Support, N.I.H., Extramural

UN SDGs

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

Publisher link

10.1111/acel.13608

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Cite this

Huan, T., Nguyen, S., Colicino, E., Ochoa-Rosales, C., Hill, W. D., Brody, J. A., Soerensen, M., Zhang, Y., Baldassari, A., Elhadad, M. A., Toshiko, T., Zheng, Y., Domingo-Relloso, A., Lee, D. H., Ma, J., Yao, C., Liu, C., Hwang, S. J., Joehanes, R., ... Levy, D. (2022). Integrative analysis of clinical and epigenetic biomarkers of mortality. Aging cell, 21(6), Article e13608. https://doi.org/10.1111/acel.13608

Huan, T, Nguyen, S, Colicino, E, Ochoa-Rosales, C, Hill, WD, Brody, JA, Soerensen, M, Zhang, Y, Baldassari, A, Elhadad, MA, Toshiko, T, Zheng, Y, Domingo-Relloso, A, Lee, DH, Ma, J, Yao, C, Liu, C, Hwang, SJ, Joehanes, R, Fornage, M, Bressler, J, van Meurs, JBJ, Debrabant, B, Mengel-From, J, Hjelmborg, J, Christensen, K, Vokonas, P, Schwartz, J, Gahrib, SA, Sotoodehnia, N, Sitlani, CM, Kunze, S, Gieger, C, Peters, A, Waldenberger, M, Deary, IJ, Ferrucci, L, Qu, Y, Greenland, P, Lloyd-Jones, DM, Hou, L, Bandinelli, S, Voortman, T, Hermann, B, Baccarelli, A, Whitsel, E, Pankow, JS & Levy, D 2022, 'Integrative analysis of clinical and epigenetic biomarkers of mortality', Aging cell, vol. 21, no. 6, e13608. https://doi.org/10.1111/acel.13608

@article{77e7c6d3b9ab42359284402701cc8d31,

title = "Integrative analysis of clinical and epigenetic biomarkers of mortality",

abstract = "DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10 -7 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, P MR = 4.1 × 10 -4 ) and negatively associated with longevity (Beta = -1.9, P MR = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk. ",

keywords = "DNA methylation, cancer, cardiovascular disease, machine learning, mortality, Cardiovascular Diseases/genetics, Epigenomics, Epigenesis, Genetic, Humans, DNA Methylation/genetics, Male, Neoplasms/genetics, Biomarkers",

author = "Tianxiao Huan and Steve Nguyen and Elena Colicino and Carolina Ochoa-Rosales and Hill, {W. David} and Brody, {Jennifer A.} and Mette Soerensen and Yan Zhang and Antoine Baldassari and Elhadad, {Mohamed Ahmed} and Tanaka Toshiko and Yinan Zheng and Arce Domingo-Relloso and Lee, {Dong Heon} and Jiantao Ma and Chen Yao and Chunyu Liu and Hwang, {Shih Jen} and Roby Joehanes and Myriam Fornage and Jan Bressler and {van Meurs}, {Joyce B.J.} and Birgit Debrabant and Jonas Mengel-From and Jacob Hjelmborg and Kaare Christensen and Pantel Vokonas and Joel Schwartz and Gahrib, {Sina A.} and Nona Sotoodehnia and Sitlani, {Colleen M.} and Sonja Kunze and Christian Gieger and Annette Peters and Melanie Waldenberger and Deary, {Ian J.} and Luigi Ferrucci and Yishu Qu and Philip Greenland and Lloyd-Jones, {Donald M.} and Lifang Hou and Stefania Bandinelli and Trudy Voortman and Brenner Hermann and Andrea Baccarelli and Eric Whitsel and Pankow, {James S.} and Daniel Levy",

note = "Funding Information: The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, National Institutes of Health, Bethesda, MD. The Cardiovascular Health Study is supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, U01HL130114, K08HL116640, R01HL087652, R01HL092111, R01HL103612, R01HL105756, R01HL103612, R01HL111089, R01HL116747 and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA), Merck Foundation/Society of Epidemiologic Research as well as Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. The DTR study was supported by The Danish Council for Independent Research—Medical Sciences (DFF-6110-00016), the European Union's Seventh Framework Programme (FP7/2007–2011) under grant Agreement No. 259679 and The Danish National Program for Research Infrastructure 2007 (09-063256). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Work in WHI was NIEHS-supported by R01-ES020836 (EAW; AB; LH). Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK{\textquoteright}s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Methylation typing was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. IJD is a member of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE), which is supported by funding from the BBSRC, the Medical Research Council (MRC), and the University of Edinburgh as part of the cross-council Lifelong Health and Wellbeing initiative (MR/K026992/1). W.D.H. is supported by a grant from Age UK (Disconnected Mind Project). The VA Normative Aging Study is sponsored by the CSP/ERIC program of the U.S. Department of Veterans Affairs and is a research component of the Massachusetts Veterans Education Research and Information Center (MAVERIC). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005. Funding was also supported by 5RC2HL102419 and R01NS087541. The authors thank the staff and participants of the ARIC study for their important contributions. J.M. is supported by a grant from NIH HL135075. W.D.H. is supported by a Career Development Award from the Medical Research Council (MRC) [MR/T030852/1] for the project titled “From genetic sequence to phenotypic consequence: genetic and environmental links between cognitive ability, socioeconomic position, and health.” The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. For a list of all the investigators who have contributed to WHI science, please visit: https://s3-us-west-2.amazonaws.com/www-whi-org/wp-content/uploads/WHI-Investigator-Long-List.pdf. Funding Information: The Framingham Heart Study is funded by National Institutes of Health contract N01‐HC‐25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, National Institutes of Health, Bethesda, MD. The Cardiovascular Health Study is supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, U01HL130114, K08HL116640, R01HL087652, R01HL092111, R01HL103612, R01HL105756, R01HL103612, R01HL111089, R01HL116747 and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA), Merck Foundation/Society of Epidemiologic Research as well as Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS‐NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. The study was supported by The Danish Council for Independent Research—Medical Sciences (DFF‐6110‐00016), the European Union's Seventh Framework Programme (FP7/2007–2011) under grant Agreement No. 259679 and The Danish National Program for Research Infrastructure 2007 (09‐063256). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Work in WHI was NIEHS‐supported by R01‐ES020836 (EAW; AB; LH). Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK{\textquoteright}s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Methylation typing was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. IJD is a member of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE), which is supported by funding from the BBSRC, the Medical Research Council (MRC), and the University of Edinburgh as part of the cross‐council Lifelong Health and Wellbeing initiative (MR/K026992/1). W.D.H. is supported by a grant from Age UK (Disconnected Mind Project). The VA Normative Aging Study is sponsored by the CSP/ERIC program of the U.S. Department of Veterans Affairs and is a research component of the Massachusetts Veterans Education Research and Information Center (MAVERIC). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005. Funding was also supported by 5RC2HL102419 and R01NS087541. The authors thank the staff and participants of the ARIC study for their important contributions. J.M. is supported by a grant from NIH HL135075. W.D.H. is supported by a Career Development Award from the Medical Research Council (MRC) [MR/T030852/1] for the project titled “From genetic sequence to phenotypic consequence: genetic and environmental links between cognitive ability, socioeconomic position, and health.” DTR Publisher Copyright: {\textcopyright} 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.",

year = "2022",

month = jun,

doi = "10.1111/acel.13608",

language = "English (US)",

volume = "21",

journal = "Aging cell",

issn = "1474-9718",

publisher = "Wiley-Blackwell",

number = "6",

}

TY - JOUR

T1 - Integrative analysis of clinical and epigenetic biomarkers of mortality

AU - Huan, Tianxiao

AU - Nguyen, Steve

AU - Colicino, Elena

AU - Ochoa-Rosales, Carolina

AU - Hill, W. David

AU - Brody, Jennifer A.

AU - Soerensen, Mette

AU - Zhang, Yan

AU - Baldassari, Antoine

AU - Elhadad, Mohamed Ahmed

AU - Toshiko, Tanaka

AU - Zheng, Yinan

AU - Domingo-Relloso, Arce

AU - Lee, Dong Heon

AU - Ma, Jiantao

AU - Yao, Chen

AU - Liu, Chunyu

AU - Hwang, Shih Jen

AU - Joehanes, Roby

AU - Fornage, Myriam

AU - Bressler, Jan

AU - van Meurs, Joyce B.J.

AU - Debrabant, Birgit

AU - Mengel-From, Jonas

AU - Hjelmborg, Jacob

AU - Christensen, Kaare

AU - Vokonas, Pantel

AU - Schwartz, Joel

AU - Gahrib, Sina A.

AU - Sotoodehnia, Nona

AU - Sitlani, Colleen M.

AU - Kunze, Sonja

AU - Gieger, Christian

AU - Peters, Annette

AU - Waldenberger, Melanie

AU - Deary, Ian J.

AU - Ferrucci, Luigi

AU - Qu, Yishu

AU - Greenland, Philip

AU - Lloyd-Jones, Donald M.

AU - Hou, Lifang

AU - Bandinelli, Stefania

AU - Voortman, Trudy

AU - Hermann, Brenner

AU - Baccarelli, Andrea

AU - Whitsel, Eric

AU - Pankow, James S.

AU - Levy, Daniel

N1 - Funding Information: The Framingham Heart Study is funded by National Institutes of Health contract N01-HC-25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, National Institutes of Health, Bethesda, MD. The Cardiovascular Health Study is supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, U01HL130114, K08HL116640, R01HL087652, R01HL092111, R01HL103612, R01HL105756, R01HL103612, R01HL111089, R01HL116747 and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA), Merck Foundation/Society of Epidemiologic Research as well as Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. The DTR study was supported by The Danish Council for Independent Research—Medical Sciences (DFF-6110-00016), the European Union's Seventh Framework Programme (FP7/2007–2011) under grant Agreement No. 259679 and The Danish National Program for Research Infrastructure 2007 (09-063256). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Work in WHI was NIEHS-supported by R01-ES020836 (EAW; AB; LH). Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Methylation typing was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. IJD is a member of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE), which is supported by funding from the BBSRC, the Medical Research Council (MRC), and the University of Edinburgh as part of the cross-council Lifelong Health and Wellbeing initiative (MR/K026992/1). W.D.H. is supported by a grant from Age UK (Disconnected Mind Project). The VA Normative Aging Study is sponsored by the CSP/ERIC program of the U.S. Department of Veterans Affairs and is a research component of the Massachusetts Veterans Education Research and Information Center (MAVERIC). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005. Funding was also supported by 5RC2HL102419 and R01NS087541. The authors thank the staff and participants of the ARIC study for their important contributions. J.M. is supported by a grant from NIH HL135075. W.D.H. is supported by a Career Development Award from the Medical Research Council (MRC) [MR/T030852/1] for the project titled “From genetic sequence to phenotypic consequence: genetic and environmental links between cognitive ability, socioeconomic position, and health.” The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. For a list of all the investigators who have contributed to WHI science, please visit: https://s3-us-west-2.amazonaws.com/www-whi-org/wp-content/uploads/WHI-Investigator-Long-List.pdf. Funding Information: The Framingham Heart Study is funded by National Institutes of Health contract N01‐HC‐25195 and HHSN268201500001I. The laboratory work for this investigation was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health. The analytical component of this project was funded by the Division of Intramural Research, National Heart, Lung, and Blood Institute, and the Center for Information Technology, National Institutes of Health, Bethesda, MD. The Cardiovascular Health Study is supported by NHLBI contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, U01HL130114, K08HL116640, R01HL087652, R01HL092111, R01HL103612, R01HL105756, R01HL103612, R01HL111089, R01HL116747 and R01HL120393 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Aging (NIA), Merck Foundation/Society of Epidemiologic Research as well as Laughlin Family, Alpha Phi Foundation, and Locke Charitable Foundation. A full list of principal CHS investigators and institutions can be found at CHS‐NHLBI.org. The provision of genotyping data was supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. Infrastructure for the CHARGE Consortium is supported in part by the National Heart, Lung, and Blood Institute grant R01HL105756. The study was supported by The Danish Council for Independent Research—Medical Sciences (DFF‐6110‐00016), the European Union's Seventh Framework Programme (FP7/2007–2011) under grant Agreement No. 259679 and The Danish National Program for Research Infrastructure 2007 (09‐063256). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Work in WHI was NIEHS‐supported by R01‐ES020836 (EAW; AB; LH). Phenotype collection in the Lothian Birth Cohort 1921 was supported by the UK’s Biotechnology and Biological Sciences Research Council (BBSRC), The Royal Society and The Chief Scientist Office of the Scottish Government. Phenotype collection in the Lothian Birth Cohort 1936 was supported by Age UK (The Disconnected Mind project). Methylation typing was supported by Centre for Cognitive Ageing and Cognitive Epidemiology (Pilot Fund award), Age UK, The Wellcome Trust Institutional Strategic Support Fund, The University of Edinburgh, and The University of Queensland. IJD is a member of the University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology (CCACE), which is supported by funding from the BBSRC, the Medical Research Council (MRC), and the University of Edinburgh as part of the cross‐council Lifelong Health and Wellbeing initiative (MR/K026992/1). W.D.H. is supported by a grant from Age UK (Disconnected Mind Project). The VA Normative Aging Study is sponsored by the CSP/ERIC program of the U.S. Department of Veterans Affairs and is a research component of the Massachusetts Veterans Education Research and Information Center (MAVERIC). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, and 75N92022D00005. Funding was also supported by 5RC2HL102419 and R01NS087541. The authors thank the staff and participants of the ARIC study for their important contributions. J.M. is supported by a grant from NIH HL135075. W.D.H. is supported by a Career Development Award from the Medical Research Council (MRC) [MR/T030852/1] for the project titled “From genetic sequence to phenotypic consequence: genetic and environmental links between cognitive ability, socioeconomic position, and health.” DTR Publisher Copyright: © 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

PY - 2022/6

Y1 - 2022/6

N2 - DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10 -7 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, P MR = 4.1 × 10 -4 ) and negatively associated with longevity (Beta = -1.9, P MR = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

AB - DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10 -7 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, P MR = 4.1 × 10 -4 ) and negatively associated with longevity (Beta = -1.9, P MR = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.

KW - DNA methylation

KW - cancer

KW - cardiovascular disease

KW - machine learning

KW - mortality

KW - Cardiovascular Diseases/genetics

KW - Epigenomics

KW - Epigenesis, Genetic

KW - Humans

KW - DNA Methylation/genetics

KW - Male

KW - Neoplasms/genetics

KW - Biomarkers

UR - http://www.scopus.com/inward/record.url?scp=85130029475&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85130029475&partnerID=8YFLogxK

U2 - 10.1111/acel.13608

DO - 10.1111/acel.13608

M3 - Article

C2 - 35546478

AN - SCOPUS:85130029475

SN - 1474-9718

VL - 21

JO - Aging cell

JF - Aging cell

IS - 6

M1 - e13608

ER -

Integrative analysis of clinical and epigenetic biomarkers of mortality

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