Association of mitochondrial DNA copy number with cardiometabolic diseases

TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

doi:10.1016/j.xgen.2021.100006

Association of mitochondrial DNA copy number with cardiometabolic diseases

TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

Laboratory Medicine and Pathology

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

17 Scopus citations

Abstract

Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole-blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: each additional 10 years of age was associated with a 0.03 SD higher level of mtDNA CN (p = 0.0014) among younger participants (younger than 65 years) versus a 0.14 SD lower level of mtDNA CN (p = 1.82 × 10⁻¹³) among older participants (65 years and older). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity (p = 5.6 × 10⁻²³⁸), hypertension (p = 2.8 × 10⁻⁵⁰), diabetes (p = 3.6 × 10⁻⁷), and hyperlipidemia (p = 6.3 × 10⁻⁵⁶). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

Original language	English (US)
Article number	100006
Journal	Cell Genomics
Volume	1
Issue number	1
DOIs	https://doi.org/10.1016/j.xgen.2021.100006
State	Published - Oct 13 2021

Bibliographical note

Funding Information:
This study did not generate any unique datasets. For the US cohorts, whole-genome sequencing data were generated by the Trans-Omics for Precision Medicine (TOPMed) program supported by National Heart, Lung, and Blood Institute. For TOPMed cohorts, mtDNA CN and phenotype data are available in the dbGaP upon request. The steps to request dbGAP access includes 1) obtain eRA Commons account, 2) obtain dbGaP access, 3) obtain access to Research Project through dbGaP, 4) grant access to individuals to your lab, and 5) log into GDC data portal. The detailed instructions can be found at the following link: ( https://gdc.cancer.gov/access-data/obtaining-access-controlled-data ). The access numbers are as follows: The Atherosclerosis Risk in Communities study, dbGaP: phs001211; The Coronary Artery Risk Development in Young Adults Study, dbGaP: phs001612; The Cardiovascular Health Study, dbGaP: phs001368; The Framingham Heart Study, dbGaP: phs000974; The Genetic Epidemiology Network of Arteriopathy, dbGaP: phs001345; The Hispanic Community Health Study/Study of Latinos, dbGaP: phs001395; The Jackson Heart Study, dbGaP: phs000964; The Multi-Ethnic Study of Atherosclerosis Study, dbGaP: phs001416; The UK Biobank data (whole-exome sequencing and phenotype data) were downloaded at https://www.ukbiobank.ac.uk/ , UKBB: 17731. Codes for association analyses in TOPMed cohorts and estimation of mtDNA CN in the UK Biobank can be accessed at https://github.com/chunyuliu1/mtDNA-copy-number-and-cardiometabolic-traits .

Funding Information:
The authors declare no competing interests, except for the disclosure from the following authors: Dr. Rocha Abecasis reports grants from National Heart Lung and Blood Institute (NIH) during the conduct of the study and personal fees and other from Regeneron Pharmaceuticals outside of the submitted work; Dr. Cupples reports personal fees from Dyslipidemia Foundation during the conduct of the study and personal fees from Veterans Administration outside of the submitted work; Dr. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson outside of the submitted work.

Funding Information:
Detailed acknowledgment for each cohort is included in the supplemental information . In brief, the authors thank the staff and participants of the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, the Coronary Artery Risk Development in Young Adults Study, the Framingham Heart Study, the Jackson Heart Study, the Genetic Epidemiology Network of Arteriopathy Study, the Hispanic Community Health Study/Study of Latinos, the Multi-Ethnic Study of Atherosclerosis Study, and the UK Biobank for their important contributions. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center ( R01HL-117626-02S1 ; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center ( R01HL-120393-02S1 ; contract HHSN268201800001I). Additional phenotype harmonization was performed by the current study ( R01AG059727 ). 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 US Department of Health and Human Services.

Funding Information:
Detailed acknowledgment for each cohort is included in the supplemental information. In brief, the authors thank the staff and participants of the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, the Coronary Artery Risk Development in Young Adults Study, the Framingham Heart Study, the Jackson Heart Study, the Genetic Epidemiology Network of Arteriopathy Study, the Hispanic Community Health Study/Study of Latinos, the Multi-Ethnic Study of Atherosclerosis Study, and the UK Biobank for their important contributions. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393-02S1; contract HHSN268201800001I). Additional phenotype harmonization was performed by the current study (R01AG059727). 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 US Department of Health and Human Services. Data preparation, X.L. R.J.L. D.E.A. C.L. K.L.W. J.C.B. L.M.R. L.F.B. W.Z. J.A.S. A.P. J.Y. X.G. N.K. B.T. M.L.G. N.B.L. A.L.F. M.F. N.P. S.R.H. and T.S.; mtDNA CN estimation, T.W.B. J.D. G.A. and D.E.A.; statistical analyses, X.L. R.J.L. D.E.A. N.K. T.S. and C.L.; manuscript preparation and revision, X.L. R.J.L. J.C.B. D.E.A. C.L. A.L.F. S.S. S.R.H. D.L. J.I.R. and B.M.P.; funding support, C.L. C.L.S. S.S.R. K.D.T. P.A.P. L.A.C. E.B. R.S.V. J.G.W. M.F. J.I.R. A.C. and B.M.P. The authors declare no competing interests, except for the disclosure from the following authors: Dr. Rocha Abecasis reports grants from National Heart Lung and Blood Institute (NIH) during the conduct of the study and personal fees and other from Regeneron Pharmaceuticals outside of the submitted work; Dr. Cupples reports personal fees from Dyslipidemia Foundation during the conduct of the study and personal fees from Veterans Administration outside of the submitted work; Dr. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson outside of the submitted work.

Publisher Copyright:
© 2021 The Author(s)

Keywords

aging
cardiometabolic disease
inflammation
mitochondrial DNA copy number
white blood cell counts
whole-exom sequencing
whole-genome sequencing

UN SDGs

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

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10.1016/j.xgen.2021.100006

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@article{f6eb19a8723443198998856f472e5e89,

title = "Association of mitochondrial DNA copy number with cardiometabolic diseases",

abstract = "Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole-blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: each additional 10 years of age was associated with a 0.03 SD higher level of mtDNA CN (p = 0.0014) among younger participants (younger than 65 years) versus a 0.14 SD lower level of mtDNA CN (p = 1.82 × 10−13) among older participants (65 years and older). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity (p = 5.6 × 10−238), hypertension (p = 2.8 × 10−50), diabetes (p = 3.6 × 10−7), and hyperlipidemia (p = 6.3 × 10−56). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.",

keywords = "aging, cardiometabolic disease, inflammation, mitochondrial DNA copy number, white blood cell counts, whole-exom sequencing, whole-genome sequencing",

author = "{TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium} and Xue Liu and Longchamps, {Ryan J.} and Wiggins, {Kerri L.} and Raffield, {Laura M.} and Bielak, {Lawrence F.} and Wei Zhao and Achilleas Pitsillides and Blackwell, {Thomas W.} and Jie Yao and Xiuqing Guo and Nuzulul Kurniansyah and Bharat Thyagarajan and Nathan Pankratz and Rich, {Stephen S.} and Taylor, {Kent D.} and Peyser, {Patricia A.} and Heckbert, {Susan R.} and Sudha Seshadri and Cupples, {L. Adrienne} and Eric Boerwinkle and Grove, {Megan L.} and Larson, {Nicholas B.} and Smith, {Jennifer A.} and Vasan, {Ramachandran S.} and Tamar Sofer and Fitzpatrick, {Annette L.} and Myriam Fornage and Jun Ding and Adolfo Correa and Goncalo Abecasis and Psaty, {Bruce M.} and Wilson, {James G.} and Daniel Levy and Rotter, {Jerome I.} and Bis, {Joshua C.} and Satizabal, {Claudia L.} and Arking, {Dan E.} and Chunyu Liu",

note = "Funding Information: This study did not generate any unique datasets. For the US cohorts, whole-genome sequencing data were generated by the Trans-Omics for Precision Medicine (TOPMed) program supported by National Heart, Lung, and Blood Institute. For TOPMed cohorts, mtDNA CN and phenotype data are available in the dbGaP upon request. The steps to request dbGAP access includes 1) obtain eRA Commons account, 2) obtain dbGaP access, 3) obtain access to Research Project through dbGaP, 4) grant access to individuals to your lab, and 5) log into GDC data portal. The detailed instructions can be found at the following link: ( https://gdc.cancer.gov/access-data/obtaining-access-controlled-data ). The access numbers are as follows: The Atherosclerosis Risk in Communities study, dbGaP: phs001211; The Coronary Artery Risk Development in Young Adults Study, dbGaP: phs001612; The Cardiovascular Health Study, dbGaP: phs001368; The Framingham Heart Study, dbGaP: phs000974; The Genetic Epidemiology Network of Arteriopathy, dbGaP: phs001345; The Hispanic Community Health Study/Study of Latinos, dbGaP: phs001395; The Jackson Heart Study, dbGaP: phs000964; The Multi-Ethnic Study of Atherosclerosis Study, dbGaP: phs001416; The UK Biobank data (whole-exome sequencing and phenotype data) were downloaded at https://www.ukbiobank.ac.uk/ , UKBB: 17731. Codes for association analyses in TOPMed cohorts and estimation of mtDNA CN in the UK Biobank can be accessed at https://github.com/chunyuliu1/mtDNA-copy-number-and-cardiometabolic-traits . Funding Information: The authors declare no competing interests, except for the disclosure from the following authors: Dr. Rocha Abecasis reports grants from National Heart Lung and Blood Institute (NIH) during the conduct of the study and personal fees and other from Regeneron Pharmaceuticals outside of the submitted work; Dr. Cupples reports personal fees from Dyslipidemia Foundation during the conduct of the study and personal fees from Veterans Administration outside of the submitted work; Dr. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson outside of the submitted work. Funding Information: Detailed acknowledgment for each cohort is included in the supplemental information . In brief, the authors thank the staff and participants of the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, the Coronary Artery Risk Development in Young Adults Study, the Framingham Heart Study, the Jackson Heart Study, the Genetic Epidemiology Network of Arteriopathy Study, the Hispanic Community Health Study/Study of Latinos, the Multi-Ethnic Study of Atherosclerosis Study, and the UK Biobank for their important contributions. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center ( R01HL-117626-02S1 ; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center ( R01HL-120393-02S1 ; contract HHSN268201800001I). Additional phenotype harmonization was performed by the current study ( R01AG059727 ). 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 US Department of Health and Human Services. Funding Information: Detailed acknowledgment for each cohort is included in the supplemental information. In brief, the authors thank the staff and participants of the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, the Coronary Artery Risk Development in Young Adults Study, the Framingham Heart Study, the Jackson Heart Study, the Genetic Epidemiology Network of Arteriopathy Study, the Hispanic Community Health Study/Study of Latinos, the Multi-Ethnic Study of Atherosclerosis Study, and the UK Biobank for their important contributions. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393-02S1; contract HHSN268201800001I). Additional phenotype harmonization was performed by the current study (R01AG059727). 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 US Department of Health and Human Services. Data preparation, X.L. R.J.L. D.E.A. C.L. K.L.W. J.C.B. L.M.R. L.F.B. W.Z. J.A.S. A.P. J.Y. X.G. N.K. B.T. M.L.G. N.B.L. A.L.F. M.F. N.P. S.R.H. and T.S.; mtDNA CN estimation, T.W.B. J.D. G.A. and D.E.A.; statistical analyses, X.L. R.J.L. D.E.A. N.K. T.S. and C.L.; manuscript preparation and revision, X.L. R.J.L. J.C.B. D.E.A. C.L. A.L.F. S.S. S.R.H. D.L. J.I.R. and B.M.P.; funding support, C.L. C.L.S. S.S.R. K.D.T. P.A.P. L.A.C. E.B. R.S.V. J.G.W. M.F. J.I.R. A.C. and B.M.P. The authors declare no competing interests, except for the disclosure from the following authors: Dr. Rocha Abecasis reports grants from National Heart Lung and Blood Institute (NIH) during the conduct of the study and personal fees and other from Regeneron Pharmaceuticals outside of the submitted work; Dr. Cupples reports personal fees from Dyslipidemia Foundation during the conduct of the study and personal fees from Veterans Administration outside of the submitted work; Dr. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson outside of the submitted work. Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = oct,

day = "13",

doi = "10.1016/j.xgen.2021.100006",

language = "English (US)",

volume = "1",

journal = "Cell Genomics",

issn = "2666-979X",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - Association of mitochondrial DNA copy number with cardiometabolic diseases

AU - TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

AU - Liu, Xue

AU - Longchamps, Ryan J.

AU - Wiggins, Kerri L.

AU - Raffield, Laura M.

AU - Bielak, Lawrence F.

AU - Zhao, Wei

AU - Pitsillides, Achilleas

AU - Blackwell, Thomas W.

AU - Yao, Jie

AU - Guo, Xiuqing

AU - Kurniansyah, Nuzulul

AU - Thyagarajan, Bharat

AU - Pankratz, Nathan

AU - Rich, Stephen S.

AU - Taylor, Kent D.

AU - Peyser, Patricia A.

AU - Heckbert, Susan R.

AU - Seshadri, Sudha

AU - Cupples, L. Adrienne

AU - Boerwinkle, Eric

AU - Grove, Megan L.

AU - Larson, Nicholas B.

AU - Smith, Jennifer A.

AU - Vasan, Ramachandran S.

AU - Sofer, Tamar

AU - Fitzpatrick, Annette L.

AU - Fornage, Myriam

AU - Ding, Jun

AU - Correa, Adolfo

AU - Abecasis, Goncalo

AU - Psaty, Bruce M.

AU - Wilson, James G.

AU - Levy, Daniel

AU - Rotter, Jerome I.

AU - Bis, Joshua C.

AU - Satizabal, Claudia L.

AU - Arking, Dan E.

AU - Liu, Chunyu

N1 - Funding Information: This study did not generate any unique datasets. For the US cohorts, whole-genome sequencing data were generated by the Trans-Omics for Precision Medicine (TOPMed) program supported by National Heart, Lung, and Blood Institute. For TOPMed cohorts, mtDNA CN and phenotype data are available in the dbGaP upon request. The steps to request dbGAP access includes 1) obtain eRA Commons account, 2) obtain dbGaP access, 3) obtain access to Research Project through dbGaP, 4) grant access to individuals to your lab, and 5) log into GDC data portal. The detailed instructions can be found at the following link: ( https://gdc.cancer.gov/access-data/obtaining-access-controlled-data ). The access numbers are as follows: The Atherosclerosis Risk in Communities study, dbGaP: phs001211; The Coronary Artery Risk Development in Young Adults Study, dbGaP: phs001612; The Cardiovascular Health Study, dbGaP: phs001368; The Framingham Heart Study, dbGaP: phs000974; The Genetic Epidemiology Network of Arteriopathy, dbGaP: phs001345; The Hispanic Community Health Study/Study of Latinos, dbGaP: phs001395; The Jackson Heart Study, dbGaP: phs000964; The Multi-Ethnic Study of Atherosclerosis Study, dbGaP: phs001416; The UK Biobank data (whole-exome sequencing and phenotype data) were downloaded at https://www.ukbiobank.ac.uk/ , UKBB: 17731. Codes for association analyses in TOPMed cohorts and estimation of mtDNA CN in the UK Biobank can be accessed at https://github.com/chunyuliu1/mtDNA-copy-number-and-cardiometabolic-traits . Funding Information: The authors declare no competing interests, except for the disclosure from the following authors: Dr. Rocha Abecasis reports grants from National Heart Lung and Blood Institute (NIH) during the conduct of the study and personal fees and other from Regeneron Pharmaceuticals outside of the submitted work; Dr. Cupples reports personal fees from Dyslipidemia Foundation during the conduct of the study and personal fees from Veterans Administration outside of the submitted work; Dr. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson outside of the submitted work. Funding Information: Detailed acknowledgment for each cohort is included in the supplemental information . In brief, the authors thank the staff and participants of the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, the Coronary Artery Risk Development in Young Adults Study, the Framingham Heart Study, the Jackson Heart Study, the Genetic Epidemiology Network of Arteriopathy Study, the Hispanic Community Health Study/Study of Latinos, the Multi-Ethnic Study of Atherosclerosis Study, and the UK Biobank for their important contributions. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center ( R01HL-117626-02S1 ; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center ( R01HL-120393-02S1 ; contract HHSN268201800001I). Additional phenotype harmonization was performed by the current study ( R01AG059727 ). 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 US Department of Health and Human Services. Funding Information: Detailed acknowledgment for each cohort is included in the supplemental information. In brief, the authors thank the staff and participants of the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, the Coronary Artery Risk Development in Young Adults Study, the Framingham Heart Study, the Jackson Heart Study, the Genetic Epidemiology Network of Arteriopathy Study, the Hispanic Community Health Study/Study of Latinos, the Multi-Ethnic Study of Atherosclerosis Study, and the UK Biobank for their important contributions. We gratefully acknowledge the studies and participants who provided biological samples and data for TOPMed. Whole-genome sequencing (WGS) for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung, and Blood Institute (NHLBI). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (R01HL-117626-02S1; contract HHSN268201800002I). Phenotype harmonization, data management, sample-identity QC, and general study coordination were provided by the TOPMed Data Coordinating Center (R01HL-120393-02S1; contract HHSN268201800001I). Additional phenotype harmonization was performed by the current study (R01AG059727). 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 US Department of Health and Human Services. Data preparation, X.L. R.J.L. D.E.A. C.L. K.L.W. J.C.B. L.M.R. L.F.B. W.Z. J.A.S. A.P. J.Y. X.G. N.K. B.T. M.L.G. N.B.L. A.L.F. M.F. N.P. S.R.H. and T.S.; mtDNA CN estimation, T.W.B. J.D. G.A. and D.E.A.; statistical analyses, X.L. R.J.L. D.E.A. N.K. T.S. and C.L.; manuscript preparation and revision, X.L. R.J.L. J.C.B. D.E.A. C.L. A.L.F. S.S. S.R.H. D.L. J.I.R. and B.M.P.; funding support, C.L. C.L.S. S.S.R. K.D.T. P.A.P. L.A.C. E.B. R.S.V. J.G.W. M.F. J.I.R. A.C. and B.M.P. The authors declare no competing interests, except for the disclosure from the following authors: Dr. Rocha Abecasis reports grants from National Heart Lung and Blood Institute (NIH) during the conduct of the study and personal fees and other from Regeneron Pharmaceuticals outside of the submitted work; Dr. Cupples reports personal fees from Dyslipidemia Foundation during the conduct of the study and personal fees from Veterans Administration outside of the submitted work; Dr. Psaty serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson outside of the submitted work. Publisher Copyright: © 2021 The Author(s)

PY - 2021/10/13

Y1 - 2021/10/13

N2 - Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole-blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: each additional 10 years of age was associated with a 0.03 SD higher level of mtDNA CN (p = 0.0014) among younger participants (younger than 65 years) versus a 0.14 SD lower level of mtDNA CN (p = 1.82 × 10−13) among older participants (65 years and older). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity (p = 5.6 × 10−238), hypertension (p = 2.8 × 10−50), diabetes (p = 3.6 × 10−7), and hyperlipidemia (p = 6.3 × 10−56). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

AB - Mitochondrial DNA (mtDNA) is present in multiple copies in human cells. We evaluated cross-sectional associations of whole-blood mtDNA copy number (CN) with several cardiometabolic disease traits in 408,361 participants of multiple ancestries in TOPMed and UK Biobank. Age showed a threshold association with mtDNA CN: each additional 10 years of age was associated with a 0.03 SD higher level of mtDNA CN (p = 0.0014) among younger participants (younger than 65 years) versus a 0.14 SD lower level of mtDNA CN (p = 1.82 × 10−13) among older participants (65 years and older). At lower mtDNA CN levels, we found age-independent associations with increased odds of obesity (p = 5.6 × 10−238), hypertension (p = 2.8 × 10−50), diabetes (p = 3.6 × 10−7), and hyperlipidemia (p = 6.3 × 10−56). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

KW - aging

KW - cardiometabolic disease

KW - inflammation

KW - mitochondrial DNA copy number

KW - white blood cell counts

KW - whole-exom sequencing

KW - whole-genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85121200823&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85121200823&partnerID=8YFLogxK

U2 - 10.1016/j.xgen.2021.100006

DO - 10.1016/j.xgen.2021.100006

M3 - Article

AN - SCOPUS:85121200823

SN - 2666-979X

VL - 1

JO - Cell Genomics

JF - Cell Genomics

IS - 1

M1 - 100006

ER -

Association of mitochondrial DNA copy number with cardiometabolic diseases

Abstract

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