Association of mitochondrial DNA copy number with cardiometabolic diseases

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

doi:10.1016/j.xgen.2021.100006

Association of mitochondrial DNA copy number with cardiometabolic diseases

Cell Genom. 2021 Oct 13;1(1):100006. doi: 10.1016/j.xgen.2021.100006.

Authors

Xue Liu¹, Ryan J Longchamps², Kerri L Wiggins³, Laura M Raffield⁴, Lawrence F Bielak⁵, Wei Zhao⁵, Achilleas Pitsillides¹, Thomas W Blackwell⁶, Jie Yao⁷, Xiuqing Guo⁷, Nuzulul Kurniansyah⁸, Bharat Thyagarajan⁹, Nathan Pankratz¹⁰, Stephen S Rich¹¹, Kent D Taylor⁷, Patricia A Peyser⁵, Susan R Heckbert¹², Sudha Seshadri^{13

14

15}, L Adrienne Cupples¹, Eric Boerwinkle^{16

17}, Megan L Grove¹⁶, Nicholas B Larson¹⁸, Jennifer A Smith⁵, Ramachandran S Vasan^{14

19}, Tamar Sofer^{8

20}, Annette L Fitzpatrick²¹, Myriam Fornage²², Jun Ding²³, Adolfo Correa²⁴, Goncalo Abecasis⁶, Bruce M Psaty^{3

25}, James G Wilson²⁶, Daniel Levy^{14

27}, Jerome I Rotter⁷, Joshua C Bis³; TOPMed mtDNA Working Group in NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium; Claudia L Satizabal^{13

14

15}, Dan E Arking², Chunyu Liu^{1

14}

Affiliations

¹ Department of Biostatistics, School of Public Health, Boston University, Boston, MA 02118, USA.
² McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, MD 21205, USA.
³ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA 98101, USA.
⁴ Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ TOPMed Informatics Research Center, University of Michigan, Ann Arbor, MI 48109, USA.
⁷ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA 90502, USA.
⁸ Division of Sleep and Circadian Disorders, Brigham and Women's Hospital, Boston, MA 02115, USA.
⁹ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
¹⁰ Department of Computational Pathology, University of Minnesota, Minneapolis, MN 55455, USA.
¹¹ Department of Public Health Services, Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908, USA.
¹² Cardiovascular Health Research Unit and Department of Epidemiology, University of Washington, Seattle, WA 98101, USA.
¹³ Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
¹⁴ Framingham Heart Study, NHLBI/NIH, Framingham, MA 01702, USA.
¹⁵ Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
¹⁶ Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
¹⁷ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
¹⁸ Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.
¹⁹ Sections of Preventive Medicine and Epidemiology, and Cardiovascular Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.
²⁰ Department of Medicine, Harvad Medical School, Boston, MA 02115, USA.
²¹ Departments of Family Medicine, Epidemiology, and Global Health, University of Washington, Seattle, WA 98195, USA.
²² Center for Human Genetics, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
²³ Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA.
²⁴ Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
²⁵ Departments of Epidemiology, and Health Services, University of Washington, Seattle, WA 98101, USA.
²⁶ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
²⁷ Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.

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: among younger participants (<65 years of age), each additional 10 years of age was associated with 0.03 standard deviation (s.d.) higher level of mtDNA CN (P = 0.0014) versus a 0.14 s.d. lower level of mtDNA CN (P = 1.82 × 10^-13) among older participants (≥65 years). 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^-5). The observed decline in mtDNA CN after 65 years of age may be a key to understanding age-related diseases.

Abstract

Grants and funding