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

TitleA genome-wide association study of mitochondrial DNA copy number in two population-based cohorts.
Publication TypeJournal Article
Year of Publication2019
AuthorsGuyatt, 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
JournalHum Genomics
Volume13
Issue1
Pagination6
Date Published2019 01 31
ISSN1479-7364
Abstract

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.

DOI10.1186/s40246-018-0190-2
Alternate JournalHum. Genomics
Citation Key10.1186/s40246-018-0190-2
PubMed ID30704525
PubMed Central IDPMC6357493
Grant List102215/2/13/2 / / Wellcome Trust / United Kingdom
MC_UU_12013/8 / / Medical Research Council / United Kingdom
WT092830M / / Wellcome Trust / United Kingdom
MR/K002767/1 / / Medical Research Council / United Kingdom
MC_UP_1501/2 / / Medical Research Council / United Kingdom
MC_UU_12013/5 / / Medical Research Council / United Kingdom
MC_PC_15018 / / Medical Research Council / United Kingdom
101876/Z/13/Z / / Wellcome Trust / United Kingdom
096919/Z/11/Z / / Wellcome Trust / United Kingdom
G0601943 / / Medical Research Council / United Kingdom
SP/07/008/24066 / / British Heart Foundation / United Kingdom
WT088806 / / Wellcome Trust / United Kingdom
G1001357 / / Medical Research Council / United Kingdom
102433/Z/13/Z / / Wellcome Trust / United Kingdom