Long-range epigenetic regulation is conferred by genetic variation located at thousands of independent loci

Lemire, Mathieu; Zaidi, Syed Hassan Ejaz; Ban, Masashi; Ge, Bing; Aïssi, Dylan; Germain, Marine; Kassam, Irfahan; Wang, Mike; Zanke, Brent W.; Morange, Pierre‐Emmanuel; Trégouët, David‐Alexandre; Wells, Philip S.; Sawcer, Stephen; Gallinger, Steven; Pastinen, Tomi; Hudson, Thomas J.

doi:10.1038/ncomms7326

Cited by 124 publications

(132 citation statements)

References 65 publications

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“…8 A study by Lemire et al demonstrated that there is extensive long-range regulation of CpG methylation associated with genetic variation. 26 The fact that CpG sites associated with a SNP were not excluded in the present study may affect heritability analysis and explain why we obtain 1,186 significant probes that give an estimated maximal heritability of 100%. To verify that, we conducted further analysis to investigate SNPs position in these probe locations using the 1,000 Genomes Project Phase 1 Version 3.…”

Section: Discussionmentioning

confidence: 83%

Familial resemblances in blood leukocyte DNA methylation levels

et al. 2016

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Section: Discussionmentioning

confidence: 83%

Familial resemblances in blood leukocyte DNA methylation levels

et al. 2016

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“…Another study quantified DNA methylation levels in lymphocytes of several hundred individuals with a chip assaying 450,000 CpG sites. This approach revealed both local ( cis ) and distant ( trans ) methylation QTLs that were in high LD to autoimmune disease variants 154 . This colocalization does not necessarily mean that the actual disease variant is affecting DNA methylation.…”

Section: Quantifying Immune-related Phenotypesmentioning

confidence: 99%

Autoimmune diseases — connecting risk alleles with molecular traits of the immune system

2016

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Genome-wide strategies have driven the discovery of more than 300 susceptibility loci for autoimmune diseases. However, for almost all loci, understanding of the mechanisms leading to autoimmunity remains limited, and most variants that are likely to be causal are in non-coding regions of the genome. A critical next step will be to identify the in vivo and ex vivo immunophenotypes that are affected by risk variants. To do this, key cell types and cell states that are implicated in autoimmune diseases will need to be defined. Functional genomic annotations from these cell types and states can then be used to resolve candidate genes and causal variants. Together with longitudinal studies, this approach may yield pivotal insights into how autoimmunity is triggered.

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“…There have been numerous reports of SNPs affecting the hypermethylation of proximal and trans-gene CpG islands, [2][3][4][5][6] Table 3. Allele frequencies for the non-hg19 SNP alleles that occur most frequently in the indicated data sets and that create or eliminate CpG's.…”

Section: Discussionmentioning

confidence: 99%

Impact of SNPs on CpG Islands in the MYC and HRAS oncogenes and in a wide variety of tumor suppressor genes: A multi-cancer approach

et al. 2016

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Single nucleotide polymorphisms (SNPs) that occur within CpG Islands may lead to increased hypermethylation if a SNP allele has the potential to form a CpG dinucleotide, as well as potentially lead to hypomethylation if a SNP allele eliminates a CpG dinucleotide. We analyzed CpG-related SNP allele frequencies in whole genome sequences (WGS) across 5 TCGA cancer datasets, thereby exploiting a more recent appreciation for signaling pathway degeneracy in cancer. The cancer data sets were analyzed for SNPs in CpG islands associated with the oncogenes, HRAS and MYC, and in the CpG islands associated with the tumor suppressor genes, APC, DCC, and RB1. We determined that one SNP allele (rs3824120) in a CpG island associated with MYC which eliminated a CpG was more common in the cancer datasets than in the 100Genomes databases (p < 0.01). For HRAS, 2 SNP alleles (rs112690925, rs7939028) that created CpG's occurred significantly less frequently in the cancer data sets than in the general SNP databases (e.g., rs7939028, p < 0.0002, in comparison with AllSNPs (142)). Also, one SNP allele (rs4940177) that created a CpG in a CpG island associated with the DCC tumor suppressor gene, was more common in the cancer datasets (p < 0.0007). To understand a broader picture of the potential of SNP alleles to create CpG's in CpG islands of tumor suppressor genes, we developed a scripted algorithm to assess the SNP alleles associated with the CpG islands of 43 tumor suppressor genes. The following tumor suppressor genes have the possibility of significant, percent increases in their CpG counts, depending on which SNP allele(s) is present: VHL, BRCA1, BRCA2, CHEK2, PTEN and RB1.

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Long-range epigenetic regulation is conferred by genetic variation located at thousands of independent loci

Cited by 124 publications

References 65 publications

Familial resemblances in blood leukocyte DNA methylation levels

Familial resemblances in blood leukocyte DNA methylation levels

Autoimmune diseases — connecting risk alleles with molecular traits of the immune system

Impact of SNPs on CpG Islands in the MYC and HRAS oncogenes and in a wide variety of tumor suppressor genes: A multi-cancer approach

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