Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality
Abstract Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of h...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41785-7 |
| _version_ | 1797558388050100224 |
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| author | Yun Soo Hong Stephanie L. Battle Wen Shi Daniela Puiu Vamsee Pillalamarri Jiaqi Xie Nathan Pankratz Nicole J. Lake Monkol Lek Jerome I. Rotter Stephen S. Rich Charles Kooperberg Alex P. Reiner Paul L. Auer Nancy Heard-Costa Chunyu Liu Meng Lai Joanne M. Murabito Daniel Levy Megan L. Grove Alvaro Alonso Richard Gibbs Shannon Dugan-Perez Lukasz P. Gondek Eliseo Guallar Dan E. Arking |
| author_facet | Yun Soo Hong Stephanie L. Battle Wen Shi Daniela Puiu Vamsee Pillalamarri Jiaqi Xie Nathan Pankratz Nicole J. Lake Monkol Lek Jerome I. Rotter Stephen S. Rich Charles Kooperberg Alex P. Reiner Paul L. Auer Nancy Heard-Costa Chunyu Liu Meng Lai Joanne M. Murabito Daniel Levy Megan L. Grove Alvaro Alonso Richard Gibbs Shannon Dugan-Perez Lukasz P. Gondek Eliseo Guallar Dan E. Arking |
| author_sort | Yun Soo Hong |
| collection | DOAJ |
| description | Abstract Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbors a particular variant. We quantify mtDNA heteroplasmy in 194,871 participants in the UK Biobank and find that heteroplasmy is associated with a 1.5-fold increased risk of all-cause mortality. Additionally, we functionally characterize mtDNA single nucleotide variants (SNVs) using a constraint-based score, mitochondrial local constraint score sum (MSS) and find it associated with all-cause mortality, and with the prevalence and incidence of cancer and cancer-related mortality, particularly leukemia. These results indicate that mitochondria may have a functional role in certain cancers, and mitochondrial heteroplasmic SNVs may serve as a prognostic marker for cancer, especially for leukemia. |
| first_indexed | 2024-03-10T17:29:48Z |
| format | Article |
| id | doaj.art-8424ec81fd124e7695c09c8c5db1a8bc |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:29:48Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-8424ec81fd124e7695c09c8c5db1a8bc2023-11-20T10:02:56ZengNature PortfolioNature Communications2041-17232023-09-0114111610.1038/s41467-023-41785-7Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortalityYun Soo Hong0Stephanie L. Battle1Wen Shi2Daniela Puiu3Vamsee Pillalamarri4Jiaqi Xie5Nathan Pankratz6Nicole J. Lake7Monkol Lek8Jerome I. Rotter9Stephen S. Rich10Charles Kooperberg11Alex P. Reiner12Paul L. Auer13Nancy Heard-Costa14Chunyu Liu15Meng Lai16Joanne M. Murabito17Daniel Levy18Megan L. Grove19Alvaro Alonso20Richard Gibbs21Shannon Dugan-Perez22Lukasz P. Gondek23Eliseo Guallar24Dan E. Arking25McKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of MedicineMcKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of MedicineMcKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of MedicineDepartment of Biomedical Engineering, Johns Hopkins UniversityMcKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of MedicineMcKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of MedicineDepartment of Laboratory Medicine and Pathology, University of MinnesotaDepartment of Genetics, Yale School of MedicineDepartment of Genetics, Yale School of MedicineThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical CenterCenter for Public Health Genomics, Department of Public Health Sciences, University of VirginiaDivision of Public Health Sciences, Fred Hutchinson Cancer Research CenterDivision of Public Health Sciences, Fred Hutchinson Cancer Research CenterDivision of Biostatistics, Institute for Health & Equity, and Cancer Center, Medical College of WisconsinDepartments of Neurology, Boston University Chobanian & Avedisian School of MedicineFramingham Heart StudyDepartment of Biostatistics, School of Public Health, Boston UniversitySection of General Internal Medicine, Boston University Chobanian & Avedisian School of MedicineNational Heart, Lung, and Blood Institute, NIHHuman Genetics Center; Department of Epidemiology, Human Genetics, and Environmental Sciences; School of Public Health, The University of Texas Health Science Center at HoustonDepartment of Epidemiology, Rollins School of Public Health, Emory UniversityHuman Genome Sequencing Center, Baylor College of MedicineHuman Genome Sequencing Center, Baylor College of MedicineDivision of Hematological Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins UniversityDepartment of Epidemiology and Medicine, and Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University Bloomberg School of Public HealthMcKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of MedicineAbstract Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbors a particular variant. We quantify mtDNA heteroplasmy in 194,871 participants in the UK Biobank and find that heteroplasmy is associated with a 1.5-fold increased risk of all-cause mortality. Additionally, we functionally characterize mtDNA single nucleotide variants (SNVs) using a constraint-based score, mitochondrial local constraint score sum (MSS) and find it associated with all-cause mortality, and with the prevalence and incidence of cancer and cancer-related mortality, particularly leukemia. These results indicate that mitochondria may have a functional role in certain cancers, and mitochondrial heteroplasmic SNVs may serve as a prognostic marker for cancer, especially for leukemia.https://doi.org/10.1038/s41467-023-41785-7 |
| spellingShingle | Yun Soo Hong Stephanie L. Battle Wen Shi Daniela Puiu Vamsee Pillalamarri Jiaqi Xie Nathan Pankratz Nicole J. Lake Monkol Lek Jerome I. Rotter Stephen S. Rich Charles Kooperberg Alex P. Reiner Paul L. Auer Nancy Heard-Costa Chunyu Liu Meng Lai Joanne M. Murabito Daniel Levy Megan L. Grove Alvaro Alonso Richard Gibbs Shannon Dugan-Perez Lukasz P. Gondek Eliseo Guallar Dan E. Arking Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality Nature Communications |
| title | Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality |
| title_full | Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality |
| title_fullStr | Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality |
| title_full_unstemmed | Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality |
| title_short | Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality |
| title_sort | deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer specific mortality |
| url | https://doi.org/10.1038/s41467-023-41785-7 |
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