Mitochondrial genome-wide analysis of nuclear DNA methylation quantitative trait loci.

Maija Lepistö, Terho Lehtimäki, Jukka T Salonen, Mika Kähönen, Olli Raitakari, Nina Hutri-Kähönen, Winfried März, Stefan Lorkowski, Pekka Ellonen, Henrikki Almusa, Jaakko Laaksonen, Graciela E Delgado, Marcus E Kleber, Leo-Pekka Lyytikäinen, Nina Mononen, Saara Marttila, Emma Raitoharju, Ilkka Seppälä, Pashupati P Mishra

Journal: Human molecular genetics 2022;31(10):1720-1732

PMID: 35077545

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Abstract

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.

Address: Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland.; Molecular Epidemiology, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland.; Gerontology Research Center, Tampere University, Tampere 33520, Finland.; Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim 68167, Germany.; Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki 00290, Finland.; Institute of Nutritional Sciences, Friedrich Schiller University Jena, Jena 07743, Germany.; Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) Halle-Jena-Leipzig, Jena 07743, Germany.; SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Augsburg 86156, Germany.; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz 8010, Austria.; Tampere Centre for Skills Training and Simulation, Tampere University, Tampere 33520, Finland.; Centre for Population Health Research, University of Turku and Turku University Hospital, Turku 20520, Finland.; Research Centre for Applied and Preventive Cardiovascular Medicine, University of Turku, Turku 20520, Finland.; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku 20520, Finland.; Department of Clinical Physiology, Tampere University Hospital, Tampere 33520, Finland.; Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere 33520, Finland.; Department of Public Health, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.; MAS-Metabolic Analytical Services Oy, Helsinki 00990, Finland.

DOI: 10.1093/hmg/ddab339

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MeSH Terms: DNA Methylation, DNA, Mitochondrial, Epigenesis, Genetic, Genome, Mitochondrial, Genome-Wide Association Study, Humans, Prediabetic State, Quantitative Trait Loci