Evidence map›Paper›PMID 41330919›Full record

ArticleNature communications2025

Epigenome-wide association study of nuclear DNA methylation in relation to mitochondrial heteroplasmy.

Meng Lai, Kyeezu Kim, Yinan Zheng, Christina A Castellani, Scott M Ratliff, Mengyao Wang, Xue Liu, Jeffrey Haessler, Tianxiao Huan, Kwadwo Bonsu and 35 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

45 authors.

Meng LaiDepartment of Biostatistics, Boston University, Boston, MA, USA.ORCID http://orcid.org/0000-0003-3666-838X
Kyeezu KimFeinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Yinan ZhengFeinberg School of Medicine, Northwestern University, Chicago, IL, USA.ORCID http://orcid.org/0000-0002-2006-7320
Christina A CastellaniDepartments of Pathology and Laboratory Medicine & Epidemiology and Biostatistics, Western University, London, ON, Canada.ORCID http://orcid.org/0000-0003-2737-0549
Scott M RatliffDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Mengyao WangDepartment of Biostatistics, Boston University, Boston, MA, USA.ORCID http://orcid.org/0009-0005-5135-0224
Xue LiuDepartment of Biostatistics, Boston University, Boston, MA, USA.ORCID http://orcid.org/0000-0002-4196-3597
Jeffrey HaesslerDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.
Tianxiao HuanPopulation Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0001-5840-9413
Kwadwo BonsuMcKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-1279-7315
Charles NewcombMcKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Kyler McKessyMcKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID http://orcid.org/0000-0002-6302-1584
Lawrence F BielakDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
Wei ZhaoDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0001-7388-0692
Roby JoehanesPopulation Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.ORCID http://orcid.org/0000-0001-5549-9054
Jiantao MaNutrition Epidemiology and Data Science, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, USA.
Xiuqing GuoThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.ORCID http://orcid.org/0000-0002-5264-5068
JoAnn E MansonDepartment of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-9426-7595
Megan L GroveHuman Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.ORCID http://orcid.org/0000-0001-6764-2508
Jan BresslerHuman Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.ORCID http://orcid.org/0000-0001-6578-4772
Kent D TaylorThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
Tuuli LappalainenNew York Genome Center, New York, NY, USA.ORCID http://orcid.org/0000-0002-7746-8109
Silva KaselaNew York Genome Center, New York, NY, USA.
Thomas W BlackwellTOPMed Informatics Research Center, University of Michigan, Ann Arbor, MI, USA.
Nicole J LakeDepartment of Genetics, Yale School of Medicine, New Haven, CT, USA.ORCID http://orcid.org/0000-0003-4103-6387
Jessica D FaulSurvey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA.
Kendra R FerrierDepartment of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.ORCID http://orcid.org/0000-0002-8813-6871
Stephen C EkkerDepartment of Pediatrics, Dell Medical School, University of Texas at Austin, Austin, TX, USA.ORCID http://orcid.org/0000-0003-0726-4212
Lifang HouFeinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Charles KooperbergDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-7986-8560
Alexander P ReinerDivision of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.ORCID http://orcid.org/0000-0002-1427-4470
Kai ZhangDepartment of Population and Community Health, College of Public Health, The University of North Texas Health Science Center at Fort Worth, Fort Worth, TX, USA.
Patricia A PeyserDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-9717-8459
Myriam FornageHuman Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.ORCID http://orcid.org/0000-0003-0677-8158
Eric BoerwinkleHuman Genetics Center, Department of Epidemiology, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Laura M RaffieldDepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-7892-193X
April P CarsonDepartment of Medicine, University of Mississippi Medical Center, Jackson, MS, USA.ORCID http://orcid.org/0000-0002-7970-6756
Stephen S RichDepartment of Genome Sciences, University of Virginia, Charlottesville, VA, USA.ORCID http://orcid.org/0000-0003-3872-7793
Yongmei LiuDepartment of Medicine, Divisions of Cardiology and Neurology, Duke University Medical Center, Durham, NC, USA.
Daniel LevyPopulation Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA.
Jerome I RotterThe Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.ORCID http://orcid.org/0000-0001-7191-1723
Jennifer A SmithDepartment of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.ORCID http://orcid.org/0000-0002-3575-5468
Dan E ArkingMcKusick-Nathans Institute, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.ORCID http://orcid.org/0000-0001-8980-8695
Chunyu LiuDepartment of Biostatistics, Boston University, Boston, MA, USA. liuc@bu.edu.ORCID http://orcid.org/0000-0002-9160-0153
NHLBI Trans-Omics for Precision Medicine (TOPMed) mtDNA Working Group

Funding

Mitochondrial DNA Copy Number and Sequence Variation in Relation to Age, Alzheimer's Disease Related Phenotypes and Age-related Metabolic TraitsR01AG059727 · NIA · BOSTON UNIVERSITY MEDICAL CAMPUS · PI LIU, CHUNYU, SATIZABAL, CLAUDIA L · 2018 to 2021
$2.6M
Mitochondrial DNA, Nuclear DNA Methylation, and Cardiometabolic Disease TraitsR01HL155569 · NHLBI · BOSTON UNIVERSITY MEDICAL CAMPUS · PI LIU, CHUNYU · 2021 to 2024
$2.4M
Mitochondrial Function and Multiomics in Aging-related Disease: Identifying Novel Biomarkers and Causal RelationshipsR01AG085753 · NIA · JOHNS HOPKINS UNIVERSITY · PI Dan E Arking · 2024 to 2026
$2.0M
Analysis of Heteroplasmic mtDNA Mutations in Whole Genome Sequencing: Methods and Application to Cardiometabolic Disease TraitsR21HL144877 · NHLBI · BOSTON UNIVERSITY MEDICAL CAMPUS · PI LIU, CHUNYU · 2019 to 2020
$246k
NHLBI NIH HHS R01 HL155569NHLBI NIH HHS R21 HL144877NIA NIH HHS R01 AG059727NIA NIH HHS R01 AG085753
6 · The paper itself

Abstract

We analyze 10,986 participants (mean age 77; 63% women; 54% non-White) across seven U.S. cohorts to study the relationship between mitochondrial DNA (mtDNA) heteroplasmy and nuclear DNA methylation. We identify 597 CpGs associated with heteroplasmy burden, generally showing lower methylation. These CpGs are enriched in dynamically regulated island shores and depleted in CpG islands, indicating involvement in context-specific rather than constitutive gene regulation. In HEK293T cells, we introduce a truncating mtDNA mutation (MT-COX3, mt.9979) and observe a positive correlation between variant allele fraction and methylation at cg04569152, supporting a direct mtDNA-nDNA epigenetic link. Many heteroplasmy-associated CpGs overlap with known methylation-trait associations for metabolic and behavioral traits. Composite CpG scores predict all-cause mortality and incident CVD, with one-unit increases associated with 1.27-fold and 1.12-fold higher hazards, respectively. These findings suggest an mtDNA-nDNA epigenetic connection in aging and disease, though its direction and mechanisms remain to be studied.

Indexed as

Cell NucleusDNA MethylationDNA, MitochondrialEpigenomeHeteroplasmyMitochondriaAgedAged, 80 and overCohort StudiesCpG IslandsEpigenesis, GeneticFemaleGenome-Wide Association StudyHEK293 CellsHumansMaleDNA, Mitochondrial

Identifiers

PMID41330919
PMCPMC12689632

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.