The correlation between CpG methylation and gene expression is driven by sequence variants.

Autor: Stefansson OA; deCODE genetics/Amgen Inc., Reykjavik, Iceland. olafurs@decode.is., Sigurpalsdottir BD; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Technology, Reykjavik University, Reykjavik, Iceland., Rognvaldsson S; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Halldorsson GH; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Juliusson K; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Sveinbjornsson G; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Gunnarsson B; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Beyter D; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Jonsson H; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Gudjonsson SA; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Olafsdottir TA; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland., Saevarsdottir S; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland., Magnusson MK; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland., Lund SH; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Tragante V; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Oddsson A; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Hardarson MT; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Technology, Reykjavik University, Reykjavik, Iceland., Eggertsson HP; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Gudmundsson RL; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Sverrisson S; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Frigge ML; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Zink F; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Holm H; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Stefansson H; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Rafnar T; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Jonsdottir I; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland., Sulem P; deCODE genetics/Amgen Inc., Reykjavik, Iceland., Helgason A; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Department of Anthropology, University of Iceland, Reykjavik, Iceland., Gudbjartsson DF; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland., Halldorsson BV; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; School of Technology, Reykjavik University, Reykjavik, Iceland., Thorsteinsdottir U; deCODE genetics/Amgen Inc., Reykjavik, Iceland.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland., Stefansson K; deCODE genetics/Amgen Inc., Reykjavik, Iceland. kstefans@decode.is.; Faculty of Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland. kstefans@decode.is.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2024 Aug; Vol. 56 (8), pp. 1624-1631. Date of Electronic Publication: 2024 Jul 24.
DOI: 10.1038/s41588-024-01851-2
Abstrakt: Gene promoter and enhancer sequences are bound by transcription factors and are depleted of methylated CpG sites (cytosines preceding guanines in DNA). The absence of methylated CpGs in these sequences typically correlates with increased gene expression, indicating a regulatory role for methylation. We used nanopore sequencing to determine haplotype-specific methylation rates of 15.3 million CpG units in 7,179 whole-blood genomes. We identified 189,178 methylation depleted sequences where three or more proximal CpGs were unmethylated on at least one haplotype. A total of 77,789 methylation depleted sequences (~41%) associated with 80,503 cis-acting sequence variants, which we termed allele-specific methylation quantitative trait loci (ASM-QTLs). RNA sequencing of 896 samples from the same blood draws used to perform nanopore sequencing showed that the ASM-QTL, that is, DNA sequence variability, drives most of the correlation found between gene expression and CpG methylation. ASM-QTLs were enriched 40.2-fold (95% confidence interval 32.2, 49.9) among sequence variants associating with hematological traits, demonstrating that ASM-QTLs are important functional units in the noncoding genome.
(© 2024. The Author(s).)
Databáze: MEDLINE
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