Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality

• Type of Material: Article
• Authors: Yun Soo Hong, Johns Hopkins University; Stephanie L Battle, Johns Hopkins University; Wen Shi, Johns Hopkins University; Daniela Puiu, Johns Hopkins University; Vamsee Pillalamarri, Johns Hopkins University; Jiaqi Xie, Johns Hopkins University; Nathan Pankratz, University of Minnesota, Minneapolis, Minnesota; Nicole J Lake, Yale University; Monkol Lek, Yale University; Jerome I Rotter, Harbor-University of California Los Angeles Medical Center, Torrance, California; Stephen S Rich, University of Virginia; Charles Kooperberg, Fred Hutchinson Cancer Research Center; Alex P Reiner, Fred Hutchinson Cancer Research Center; Paul L Auer, Medical College of Wisconsin; Nancy Heard-Costa, Boston University; Chunyu Liu, Boston University; Meng Lai, Boston University; Joanne M Murabito, Boston University; Daniel Levy, National Heart, Lung, and Blood Institute; Megan L Grove, University of Texas, Houston, Texas; Alvaro Alonso, Emory University; Richard Gibbs, Baylor College of Medicine; Shannon Dugan-Perez, Baylor College of Medicine; Lukasz P Gondek, Johns Hopkins University; Eliseo Guallar, Johns Hopkins University; Dan E Arking, Johns Hopkins University
• Language: English
• Date: 2023-09-30
• Publisher: Springer Nature
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2023, The Author(s)
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1038/s41467-023-41785-7
• Title of Journal or Parent Work: Nature Communications
• Volume: 12
• Start Page: 6113
• Grant/Funding Information: This research was conducted using the UK Biobank Resource under Application Number 17731. This work was supported by National Heart, Lung and Blood Institute, National Institutes of Health (NIH) grants R01HL144569 (D.E.A) and K24HL148521 (A.A.), National Institute on Aging grants R01AG059727/R01HL15569 (C.L.), NHLBI: R01HL156144 (L.P.G.), National Health and Medical Research Council Fellowship (1159456) and American Australian Association Scholarship (N.J.L). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Molecular data for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for “NHLBI TOPMed: Atherosclerosis Risk in Communities (ARIC) (phs001211) was performed at the Baylor College of Medicine Human Genome Sequencing Center (HHSN268201500015C and 3U54HG003273-12S2) and the Broad Institute for MIT and Harvard (3R01HL092577- 06S1). 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, was 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. The Genome Sequencing Program (GSP) was funded by the National Human Genome Research Institute (NHGRI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Eye Institute (NEI). The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. The Centers for Common Disease Genomics (CCDG) program was supported by NHGRI and NHLBI, and WGS was performed at the Baylor College of Medicine Human Genome Sequencing Center (UM1 HG008898). The Analysis Commons was funded by R01HL131136. WGS for the Trans-Omics in Precision Medicine (TOPMed) program was supported by the National Heart, Lung and Blood Institute (NHLBI). WGS for “NHLBI TOPMed: Multi-Ethnic Study of Atherosclerosis (MESA)” (phs001416.v1.p1) was performed at the Broad Institute of MIT and Harvard (3U54HG003067-13S1). Centralized read mapping and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed Informatics Research Center (3R01HL-117626-02S1). Phenotype harmonization, data management, sample-identity QC, and general study coordination, were provided by the TOPMed Data Coordinating Center (3R01HL-120393-02S1), and TOPMed MESA Multi-Omics (HHSN2682015000031/HSN26800004). The MESA projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for the Multi-Ethnic Study of Atherosclerosis (MESA) projects are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1TR001881, DK063491, and R01HL105756. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutes can be found at http://www.mesa-nhlbi.org. WGS for “NHLBI TOPMed: Framingham Heart Study (FHS)” (phs000974) was performed at the Broad Institute of MIT and Harvard (3R01HL092577-06S1 and 3U54HG003067-12S2). 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, was provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I). WGS for “NHLBI TOPMed: Women’s Health Initiative (WHI)” (phs001237) was performed at the Broad Institute of MIT and Harvard (HHSN268201500014C). 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 was provided by the TOPMed Data Coordinating Center (R01HL-120393; U01HL-120393; contract HHSN268201800001I).
• Keywords: Genetic markers; mtDNA; Genetics research; Leukaemia; Mitochondria
• Research Categories: Biology, Genetics; Health Sciences, Oncology; Health Sciences, Medicine and Surgery

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. Mitochondrial DNA is known to exhibit heterogeneity of variants, even within a single cell. Here, the authors assessed this heteroplasmy of mitochondrial DNA within the UK Biobank cohort and showed that the presence of heteroplasmy and a functional score generated from heteroplasmic SNVs were associated with all-cause mortality and certain cancers.