Mitochondrial genome-wide analysis of nuclear DNA methylation quantitative trait loci
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 t...
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| Veröffentlicht in: | Human molecular genetics 2022-05, Vol.31 (10), p.1720-1732 |
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| container_title | Human molecular genetics |
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| creator | 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 |
| description | 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 |
| doi_str_mv | 10.1093/hmg/ddab339 |
| format | Article |
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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.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddab339</identifier><identifier>PMID: 35077545</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Association Studies ; DNA Methylation - genetics ; DNA, Mitochondrial - genetics ; Epigenesis, Genetic ; Genome, Mitochondrial - genetics ; Genome-Wide Association Study - methods ; Humans ; Prediabetic State - genetics ; Quantitative Trait Loci - genetics</subject><ispartof>Human molecular genetics, 2022-05, Vol.31 (10), p.1720-1732</ispartof><rights>The Author(s) 2021. Published by Oxford University Press.</rights><rights>The Author(s) 2021. Published by Oxford University Press. 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c381t-b7d3ad223c3ae96144c4f6c43ba204b6b7f20e77b9a158e1b608d1f4aebd06613</citedby><cites>FETCH-LOGICAL-c381t-b7d3ad223c3ae96144c4f6c43ba204b6b7f20e77b9a158e1b608d1f4aebd06613</cites><orcidid>0000-0002-9649-840X ; 0000-0003-3577-6928</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35077545$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Laaksonen, Jaakko</creatorcontrib><creatorcontrib>Mishra, Pashupati P</creatorcontrib><creatorcontrib>Seppälä, Ilkka</creatorcontrib><creatorcontrib>Raitoharju, Emma</creatorcontrib><creatorcontrib>Marttila, Saara</creatorcontrib><creatorcontrib>Mononen, Nina</creatorcontrib><creatorcontrib>Lyytikäinen, Leo-Pekka</creatorcontrib><creatorcontrib>Kleber, Marcus E</creatorcontrib><creatorcontrib>Delgado, Graciela E</creatorcontrib><creatorcontrib>Lepistö, Maija</creatorcontrib><creatorcontrib>Almusa, Henrikki</creatorcontrib><creatorcontrib>Ellonen, Pekka</creatorcontrib><creatorcontrib>Lorkowski, Stefan</creatorcontrib><creatorcontrib>März, Winfried</creatorcontrib><creatorcontrib>Hutri-Kähönen, Nina</creatorcontrib><creatorcontrib>Raitakari, Olli</creatorcontrib><creatorcontrib>Kähönen, Mika</creatorcontrib><creatorcontrib>Salonen, Jukka T</creatorcontrib><creatorcontrib>Lehtimäki, Terho</creatorcontrib><title>Mitochondrial genome-wide analysis of nuclear DNA methylation quantitative trait loci</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>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.</description><subject>Association Studies</subject><subject>DNA Methylation - genetics</subject><subject>DNA, Mitochondrial - genetics</subject><subject>Epigenesis, Genetic</subject><subject>Genome, Mitochondrial - genetics</subject><subject>Genome-Wide Association Study - methods</subject><subject>Humans</subject><subject>Prediabetic State - genetics</subject><subject>Quantitative Trait Loci - genetics</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkc1P3DAQxa2qFSyUU--Vj5WqFH_F2VwqISgtEm0v5WyN7cmuK8eG2KHa_54gtghOo9H89N7TPEI-cPaFs16ebsfNqfdgpezfkBVXmjWCreVbsmK9Vo3umT4kR6X8ZYxrJbsDcihb1nWtalfk5meo2W1z8lOASDeY8ojNv-CRQoK4K6HQPNA0u4gw0YtfZ3TEut1FqCEnejdDqqEuyz3SOkGoNGYX3pN3A8SCJ_t5TG4uv_05_9Fc__5-dX523Ti55rWxnZfghZBOAvaaK-XUoJ2SFgRTVttuEAy7zvbA2zVyq9na80EBWs-05vKYfH3SvZ3tiN5hWjJEczuFEaadyRDM60sKW7PJ96bnQuhWLgKf9gJTvpuxVDOG4jBGSJjnYoQWotdSsEevz0-om3IpEw7PNpyZxyLMUoTZF7HQH18me2b_f14-ANk8h68</recordid><startdate>20220519</startdate><enddate>20220519</enddate><creator>Laaksonen, Jaakko</creator><creator>Mishra, Pashupati P</creator><creator>Seppälä, Ilkka</creator><creator>Raitoharju, Emma</creator><creator>Marttila, Saara</creator><creator>Mononen, Nina</creator><creator>Lyytikäinen, Leo-Pekka</creator><creator>Kleber, Marcus E</creator><creator>Delgado, Graciela E</creator><creator>Lepistö, Maija</creator><creator>Almusa, Henrikki</creator><creator>Ellonen, Pekka</creator><creator>Lorkowski, Stefan</creator><creator>März, Winfried</creator><creator>Hutri-Kähönen, Nina</creator><creator>Raitakari, Olli</creator><creator>Kähönen, Mika</creator><creator>Salonen, Jukka T</creator><creator>Lehtimäki, Terho</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-9649-840X</orcidid><orcidid>https://orcid.org/0000-0003-3577-6928</orcidid></search><sort><creationdate>20220519</creationdate><title>Mitochondrial genome-wide analysis of nuclear DNA methylation quantitative trait loci</title><author>Laaksonen, Jaakko ; 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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.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>35077545</pmid><doi>10.1093/hmg/ddab339</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-9649-840X</orcidid><orcidid>https://orcid.org/0000-0003-3577-6928</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Association Studies DNA Methylation - genetics DNA, Mitochondrial - genetics Epigenesis, Genetic Genome, Mitochondrial - genetics Genome-Wide Association Study - methods Humans Prediabetic State - genetics Quantitative Trait Loci - genetics |
| title | Mitochondrial genome-wide analysis of nuclear DNA methylation quantitative trait loci |
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