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| PMID |
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| TITLE |
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| Rare genetic variants underlie outlying levels of DNA methylation and gene-expression. |
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| ABSTRACT |
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| Testing the effect of rare variants on phenotypic variation is difficult due to the need for extremely large cohorts to identify associated variants given expected effect sizes. An alternative approach is to investigate the effect of rare genetic variants on DNA methylation (DNAm) as effect sizes are expected to be larger for molecular traits compared to complex traits. Here, we investigate DNAm in healthy ageing populations-the Lothian Birth Cohorts of 1921 and 1936 and identify both transient and stable outlying DNAm levels across the genome. We find an enrichment of rare genetic single nucleotide polymorphisms (SNPs) within 1 kb of DNAm sites in individuals with stable outlying DNAm, implying genetic control of this extreme variation. Using a family-based cohort, the Brisbane Systems Genetics Study, we observed increased sharing of DNAm outliers among more closely related individuals, consistent with these outliers being driven by rare genetic variation. We demonstrated that outlying DNAm levels have a functional consequence on gene expression levels, with extreme levels of DNAm being associated with gene expression levels towards the tails of the population distribution. This study demonstrates the role of rare SNPs in the phenotypic variation of DNAm, and the effect of extreme levels of DNAm on gene expression. |
| © The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| entrez |
2023/02/15 08:33 |
| pubmed |
2023/02/16 06:00 |
| medline |
2023/02/16 06:00 |
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| AUTHORS |
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| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Chundru VK |
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Chundru |
V Kartik |
VK |
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Wellcome Sanger Institute, Hinxton CB10 1RQ, UK. |
| Marioni RE |
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Marioni |
Riccardo E |
RE |
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Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh EH4 2XU, UK. |
| Pendergast JGD |
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Pendergast |
James G D |
JGD |
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The Roslin Institute, The University of Edinburgh, Midlothian EH25 9RG, UK. |
| Lin T |
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Lin |
Tian |
T |
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Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. |
| Beveridge AJ |
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Beveridge |
Allan J |
AJ |
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Glasgow Polyomics, Wolfson Wohl Cancer Research Centre, The University of Glasgow, Glasgow G61 1QH, UK. |
| Martin NG |
|
Martin |
Nicholas G |
NG |
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QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia. |
| Montgomery GW |
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Montgomery |
Grant W |
GW |
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Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. |
| Hume DA |
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Hume |
David A |
DA |
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Mater Research Institute, The University of Queensland, Brisbane, Qld 4102, Australia. |
| Deary IJ |
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Deary |
Ian J |
IJ |
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Lothian Birth Cohorts, Department of Psychology, The University of Edinburgh, Edinburgh EH8 9JZ, UK. |
| Visscher PM |
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Visscher |
Peter M |
PM |
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Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. |
| Wray NR |
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Wray |
Naomi R |
NR |
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Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. |
| McRae AF |
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McRae |
Allan F |
AF |
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Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia. |
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| INVESTIGATORS |
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| JOURNAL |
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| VOLUME: |
| ISSUE: |
| TITLE: Human molecular genetics |
| ISOABBREVIATION: Hum Mol Genet |
| YEAR: 2023 |
| MONTH: Feb |
| DAY: 15 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1460-2083 |
| ISSNTYPE: Electronic |
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| MEDLINE JOURNAL |
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| MEDLINETA: Hum Mol Genet |
| COUNTRY: England |
| ISSNLINKING: 0964-6906 |
| NLMUNIQUEID: 9208958 |
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| PUBLICATION TYPE |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
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| COMMENTS AND CORRECTIONS |
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| CHEMICALS |
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