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A genome-wide association study of mitochondrial DNA copy number in two population-based cohorts

Lookup NU author(s): Rebecca Brennan, Dr Angela Pyle, Professor Heather Cordell, Professor Patrick Chinnery, Dr Gavin Hudson



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


BACKGROUND: Mitochondrial DNA copy number (mtDNA CN) exhibits interindividual and intercellular variation, but few genome-wide association studies (GWAS) of directly assayed mtDNA CN exist. We undertook a GWAS of qPCR-assayed mtDNA CN in the Avon Longitudinal Study of Parents and Children (ALSPAC) and the UK Blood Service (UKBS) cohort. After validating and harmonising data, 5461 ALSPAC mothers (16-43 years at mtDNA CN assay) and 1338 UKBS females (17-69 years) were included in a meta-analysis. Sensitivity analyses restricted to females with white cell-extracted DNA and adjusted for estimated or assayed cell proportions. Associations were also explored in ALSPAC children and UKBS males. RESULTS: A neutrophil-associated locus approached genome-wide significance (rs709591 [MED24], β (change in SD units of mtDNA CN per allele) [SE] - 0.084 [0.016], p = 1.54e-07) in the main meta-analysis of adult females. This association was concordant in magnitude and direction in UKBS males and ALSPAC neonates. SNPs in and around ABHD8 were associated with mtDNA CN in ALSPAC neonates (rs10424198, β [SE] 0.262 [0.034], p = 1.40e-14), but not other study groups. In a meta-analysis of unrelated individuals (N = 11,253), we replicated a published association in TFAM (β [SE] 0.046 [0.017], p = 0.006), with an effect size much smaller than that observed in the replication analysis of a previous in silico GWAS. CONCLUSIONS: In a hypothesis-generating GWAS, we confirm an association between TFAM and mtDNA CN and present putative loci requiring replication in much larger samples. We discuss the limitations of our work, in terms of measurement error and cellular heterogeneity, and highlight the need for larger studies to better understand nuclear genomic control of mtDNA copy number.

Publication metadata

Author(s): Guyatt AL, Brennan RR, Burrows K, Guthrie PAI, Ascione R, Ring SM, Gaunt TR, Pyle A, Cordell HJ, Lawlor DA, Chinnery PF, Hudson G, Rodriguez S

Publication type: Article

Publication status: Published

Journal: Human Genomics

Year: 2019

Volume: 13

Online publication date: 31/01/2019

Acceptance date: 27/12/2018

Date deposited: 11/02/2019

ISSN (electronic): 1479-7364

Publisher: BioMed Central Ltd


DOI: 10.1186/s40246-018-0190-2

PubMed id: 30704525


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Funder referenceFunder name
096919/Z/11/ZWellcome Trust
101876/Z/13/ZWellcome Trust
F-1202Parkinson`s UK (formerly Parkinson`s Disease Society)
SP/07/008/ 24066