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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Guyatt, Anna L 
Brennan, Rebecca R 
Burrows, Kimberley 
Guthrie, Philip AI 
Ascione, Raimondo 

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.

Description

Keywords

ALSPAC, Complex traits, Genetic epidemiology, Genome-wide association study, Mitochondrial DNA, Adolescent, Adult, Child, Cohort Studies, DNA Copy Number Variations, DNA, Mitochondrial, Female, Genome-Wide Association Study, Humans, Infant, Newborn, Male, Middle Aged, Polymorphism, Single Nucleotide

Journal Title

Hum Genomics

Conference Name

Journal ISSN

1473-9542
1479-7364

Volume Title

13

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (101876/Z/13/Z)
Wellcome Trust (101876/B/13/A)
WBH Foundation (via Cambridge in America) (Unknown)
Wellcome Trust (212219/Z/18/Z)
Medical Research Council (MC_UU_00015/8)
MRC (MC_UU_00015/8)
Medical Research Council (MC_UU_00015/7)
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