Discovery of mitochondrial DNA variants associated with genome-wide blood cell gene expression: a population-based mtDNA sequencing study

Laaksonen, Jaakko; Seppälä, Ilkka; Raitoharju, Emma; Mononen, Nina; Lyytikäinen, Leo-Pekka; Waldenberger, Mélanie; Illig, Thomas; Lepistö, Maija; Almusa, Henrikki; Ellonen, Pekka; Hutri‐Kähönen, Nina; Juonala, Markus; Kähönen, Mika; Raitakari, Olli T.; Salonen, Jukka T.; Lehtimäki, Terho

doi:10.1093/hmg/ddz011

Cited by 3 publications

(5 citation statements)

References 36 publications

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“…We did not observe differential methylation at CpG sites mapping to the genes that showed mtSNP- or haplogroup-specific transcriptome profiles in Kassam et al . ( 5 ) or in our previous study ( 6 ). In addition, variant m.3480A>G was strongly associated with nuclear DNA transcripts in both of these previous studies but was not significantly associated with DNAm at any stage in the present study.…”

Section: Discussionmentioning

confidence: 64%

“…This hypothesis has been tested in Drosophila melanogaster in which a strong effect of mtSNPs on gene expression was observed only in males, while the mitochondrial effect in females was negligible ( 32 ). In humans, there is no evidence of sex-specific mitochondrial genetic control of peripheral blood gene expression ( 5 , 6 ). Even though sex-specific DNAm patterns have been demonstrated in peripheral blood ( 33 , 34 ), our results imply that, similarly to gene expression, mtDNA variation has the same genetic effect on peripheral blood DNAm in both sexes.…”

Section: Discussionmentioning

confidence: 99%

“…The expression data were analyzed using the Illumina HumanHT-12 v4 Expression BeadChip. The procedures have been described previously ( 6 ).…”

Section: Methodsmentioning

confidence: 99%

“…Retrograde signals from mitochondria to the nucleus induce changes in, for example, nuclear DNA methylation (DNAm) and gene expression, which, in turn, can regulate mitochondrial functionality and metabolism ( 3 , 4 ). Previous cohort-level studies have shown that mtSNPs and haplogroups also associate with nuclear gene expression in peripheral blood ( 5 , 6 ). If the associations arose from causal relationships, they could have been mediated by epigenetic changes.…”

Section: Introductionmentioning

confidence: 99%

“…Although mtSNPs and haplogroups do not seem to be associated with prediabetes or T2D in the European population ( 15–17 ), they may have smaller consequences on a molecular level or modulate the complications of the disease ( 18 ). For example, we have demonstrated that the onset of prediabetes may lead to changes in the mitochondrial genetic control of the peripheral blood transcriptome ( 6 ). However, the crosstalk between mtDNA and the nuclear epigenome in the setting of prediabetes is not known.…”

Section: Introductionmentioning

confidence: 99%

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

Laaksonen

Mishra

Seppälä

et al. 2021

Human Molecular Genetics

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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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Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

“…The expression data were analyzed using the Illumina HumanHT-12 v4 Expression BeadChip. The procedures have been described previously ( 6 ).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Laaksonen

Mishra

Seppälä

et al. 2021

Human Molecular Genetics

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Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts

Laaksonen

Mishra

Seppälä

et al. 2021

Sci Rep

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High blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.

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The role of genetics and epigenetics in sex differences in human survival

Bacalini

Franceschi

Giuliani

2023

Genus

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Sex differences in human survival have been extensively investigated in many studies that have in part uncovered the biological determinants that promote a longer life in females with respect to males. Moreover, researches performed in the past years have prompted increased awareness about the biological effects of environmental factors that can modulate the magnitude of the sex gap in survival. Besides the genetic background, epigenetic modifications like DNA methylation, that can modulate cell function, have been particularly studied in this framework. In this review, we aim to summarize the role of the genetic and epigenetic mechanisms in promoting female advantage from the early in life (“INNATE” features), and in influencing the magnitude of the gap in sex differences in survival and ageing (“VARIABLE” features). After briefly discussing the biological bases of sex determination in humans, we will provide much evidence showing that (i) “innate” mechanisms common to all males and to all females (both genetic and epigenetic) play a major role in sex differences in lifespan; (ii) “variable” genetic and epigenetic patterns, that vary according to context, populations and exposures to different environments, can affect the magnitude of the gap in sex differences in survival. Then we will describe recent findings in the use of epigenetic clocks to uncover sex differences in biological age and thus potentially in mortality. In conclusion, we will discuss how environmental factors cannot be kept apart from the biological factors providing evidence from the field of human ecology.

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Discovery of mitochondrial DNA variants associated with genome-wide blood cell gene expression: a population-based mtDNA sequencing study

Cited by 3 publications

References 36 publications

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

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

Examining the effect of mitochondrial DNA variants on blood pressure in two Finnish cohorts

The role of genetics and epigenetics in sex differences in human survival

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