The correlation between CpG methylation and gene expression is driven by sequence variants
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Published:2024-07-24
Issue:8
Volume:56
Page:1624-1631
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ISSN:1061-4036
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Container-title:Nature Genetics
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language:en
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Short-container-title:Nat Genet
Author:
Stefansson Olafur AndriORCID, Sigurpalsdottir Brynja DoggORCID, Rognvaldsson Solvi, Halldorsson Gisli HreinnORCID, Juliusson Kristinn, Sveinbjornsson GardarORCID, Gunnarsson Bjarni, Beyter Doruk, Jonsson HakonORCID, Gudjonsson Sigurjon Axel, Olafsdottir Thorunn AstaORCID, Saevarsdottir SaedisORCID, Magnusson Magnus KarlORCID, Lund Sigrun HelgaORCID, Tragante ViniciusORCID, Oddsson AsmundurORCID, Hardarson Marteinn ThorORCID, Eggertsson Hannes PeturORCID, Gudmundsson Reynir L., Sverrisson Sverrir, Frigge Michael L.ORCID, Zink Florian, Holm HilmaORCID, Stefansson Hreinn, Rafnar ThorunnORCID, Jonsdottir IngileifORCID, Sulem PatrickORCID, Helgason AgnarORCID, Gudbjartsson Daniel F.ORCID, Halldorsson Bjarni V.ORCID, Thorsteinsdottir Unnur, Stefansson KariORCID
Abstract
AbstractGene 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.
Publisher
Springer Science and Business Media LLC
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