Journal
HUMAN MOLECULAR GENETICS
Volume 31, Issue 10, Pages 1720-1732Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddab339
Keywords
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Funding
- Juhani Aho Foundation
- Aarne Koskelo Foundation
- Finnish Medical Foundation
- Academy of Finland [322098, 330809, 338395, 286284, 134309, 126925, 121584, 124282, 129378, 117787, 41071]
- Kela Social Insurance Institution of Finland
- Competitive State Research Financing of the Expert Responsibility Area of Kuopio
- Turku University Hospitals [X51001]
- Juho Vainio Foundation
- Paavo Nurmi Foundation
- Finnish Foundation for Cardiovascular Research
- Finnish Cultural Foundation
- Sigrid Juselius Foundation
- Tampere Tuberculosis Foundation
- Emil Aaltonen Foundation
- Yrjo Jahnsson Foundation
- Signe and Ane Gyllenberg Foundation
- Diabetes Research Foundation of the Finnish Diabetes Association
- EU [848146, 755320]
- European Research Council [742927]
- Tampere University Hospital Supporting Foundation
- Finnish Society of Clinical Chemistry
- German Federal Ministry for Education and Research (BMBF) [01EA1808A, 01EA1411A]
- German Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD)
- Tampere University Hospital within the framework of the German Competence Cluster for Nutrition and Cardiovascular Health (nutriCARD) (Halle-Jena-Leipzig) [X51001]
- Laboratoriolaaketieteen edistamissaatio
- Academy of Finland (AKA) [330809, 330809] Funding Source: Academy of Finland (AKA)
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This study provides evidence for a genetic control of nuclear DNA methylation by mitochondria, with little evidence found for sex- and prediabetes-specific effects. However, a limitation of our study is the lack of a comparable mtDNA dataset, and further studies are needed to validate our results.
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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