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

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dc.contributor.authorGuyatt, A.L.
dc.contributor.authorBrennan, R.R.
dc.contributor.authorBurrows, K.
dc.contributor.authorGuthrie, P.A.I.
dc.contributor.authorAscione, R.
dc.contributor.authorRing, S.M.
dc.contributor.authorGaunt, T.R.
dc.contributor.authorPyle, A.
dc.contributor.authorCordell, H.J.
dc.contributor.authorLawlor, D.A.
dc.contributor.authorChinnery, P.F.
dc.contributor.authorHudson, G.
dc.contributor.authorRodriguez, S.
dc.date.issued2019
dc.description.abstractBACKGROUND: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.
dc.description.statementofresponsibilityAnna L. Guyatt, Rebecca R. Brennan, Kimberley Burrows, Philip A. I. Guthrie, Raimondo Ascione ... Debbie A. Lawlor ... et al.
dc.identifier.citationHuman Genomics, 2019; 13(1):6-6
dc.identifier.doi10.1186/s40246-018-0190-2
dc.identifier.issn1479-7364
dc.identifier.issn1479-7364
dc.identifier.orcidLawlor, D.A. [0000-0002-6793-2262]
dc.identifier.urihttp://hdl.handle.net/2440/126583
dc.language.isoen
dc.publisherBioMed Central
dc.rights© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
dc.source.urihttps://doi.org/10.1186/s40246-018-0190-2
dc.subjectMitochondrial DNA; ALSPAC; genome-wide association study; complex traits; genetic epidemiology
dc.titleA genome-wide association study of mitochondrial DNA copy number in two population-based cohorts
dc.typeJournal article
pubs.publication-statusPublished

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