Refereed journal article or data article (A1)
Mitochondrial genome-wide analysis of nuclear DNA methylation quantitative trait loci
List of Authors: Laaksonen Jaakko, Mishra Pashupati P., Seppälä Ilkka, Raitoharju Emma, Marttila Saara, Mononen Nina, Lyytikäinen Leo-Pekka, Kleber Marcus E., Delgado Graciela E., Lepistö Maija, Almusa Henrikki, Ellonen Pekka, Lorkowski Stefan, März Winfried, Hutri-Kähönen Nina, Raitakari Olli, Kähönen Mika, Salonen Jukka T., Lehtimäki Terho
Publisher: OXFORD UNIV PRESS
Publication year: 2022
Journal: Human Molecular Genetics
Journal acronym: HUM MOL GENET
Volume number: 31
Issue number: 10
Start page: 1720
End page: 1732
Number of pages: 13
ISSN: 0964-6906
eISSN: 1460-2083
DOI: http://dx.doi.org/10.1093/hmg/ddab339
URL: https://academic.oup.com/hmg/article/31/10/1720/6431953
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/175609269
Mitochondria have a complex communication network with the surrounding cell and can alter nuclear DNA methylation (DNAm). Variation in the mitochondrial DNA (mtDNA) has also been linked to differential DNAm. Genome-wide association studies have identified numerous DNAm quantitative trait loci, but these studies have not examined the mitochondrial genome. Herein, we quantified nuclear DNAm from blood and conducted a mitochondrial genome-wide association study of DNAm, with an additional emphasis on sex- and prediabetes-specific heterogeneity. We used the Young Finns Study (n = 926) with sequenced mtDNA genotypes as a discovery sample and sought replication in the Ludwigshafen Risk and Cardiovascular Health study (n = 2317). We identified numerous significant associations in the discovery phase (P < 10(-9)), but they were not replicated when accounting for multiple testing. In total, 27 associations were nominally replicated with a P < 0.05. The replication analysis presented no evidence of sex- or prediabetes-specific heterogeneity. The 27 associations were included in a joint meta-analysis of the two cohorts, and 19 DNAm sites associated with mtDNA variants, while four other sites showed haplogroup associations. An expression quantitative trait methylation analysis was performed for the identified DNAm sites, pinpointing two statistically significant associations. This study provides evidence of a mitochondrial genetic control of nuclear DNAm with little evidence found for sex- and prediabetes-specific effects. The lack of a comparable mtDNA data set for replication is a limitation in our study and further studies are needed to validate our results.
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