Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers

Voisin, Sarah; Almén, Markus Sällman; Zheleznyakova, Galina Yurevna; Lundberg, Lina; Zarei, Sanaz; Castillo, Sandra; Eriksson, Fia Ence; Nilsson, Emil; Blüher, Matthias; Böttcher, Yvonne; Kovacs, Peter; Kloviņš, Jānis; Rask‐Andersen, Mathias; Schiöth, Helgi B.

doi:10.1186/s13073-015-0225-4

Cited by 134 publications

(101 citation statements)

References 84 publications

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“…Early evidence demonstrated that the risk allele of FTO promotes increased methylation of sites within intron 1 of the FTO gene, as well as greater methylation of additional genes [257]. Other evidence identified 28 obesity-associated SNPs that were associated with differential methylation at 107 proximal CpG sites [258]. A recent study of Trim28 haploinsufficiency used findings from mice and humans to demonstrate the variation in obesity phenotypes that can be induced through epigenetic changes [259].…”

Section: Biological Processes Underlying Statistical Gene-environmentmentioning

confidence: 96%

“…In order to refine the search for interaction variants, statistical GEI tests could be combined with methylation quantitative trait loci (meQTL), expression quantitative trait loci (eQTL), and protein quantitative trait loci (pQTL) to focus on SNPs with a plausible biological mechanism for interaction [258]. Specifically, a joint test could be applied to (1) identify genetic variants that statistically interact with a given environmental exposure (e.g.…”

Section: Future Directions For Gene-environment Interactions and Obesitymentioning

confidence: 99%

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The importance of gene–environment interactions in human obesity

2016

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The worldwide obesity epidemic has been mainly attributed to lifestyle changes. However, who becomes obese in an obesity-prone environment is largely determined by genetic factors. In the last 20 years, important progress has been made in the elucidation of the genetic architecture of obesity. In parallel with successful gene identifications, the number of gene-environment interaction (GEI) studies has grown rapidly. This paper reviews the growing body of evidence supporting gene-environment interactions in the field of obesity. Heritability, monogenic and polygenic obesity studies provide converging evidence that obesity-predisposing genes interact with a variety of environmental, lifestyle and treatment exposures. However, some skepticism remains regarding the validity of these studies based on several issues, which include statistical modelling, confounding, low replication rate, underpowered analyses, biological assumptions and measurement precision. What follows in this review includes (1) an introduction to the study of GEI, (2) the evidence of GEI in the field of obesity, (3) an outline of the biological mechanisms that may explain these interaction effects, (4) methodological challenges associated with GEI studies and potential solutions, and (5) future directions of GEI research. Thus far, this growing body of evidence has provided a deeper understanding of GEI influencing obesity and may have tremendous applications in the emerging field of personalized medicine and individualized lifestyle recommendations.

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Section: Biological Processes Underlying Statistical Gene-environmentmentioning

confidence: 96%

Section: Future Directions For Gene-environment Interactions and Obesitymentioning

confidence: 99%

The importance of gene–environment interactions in human obesity

2016

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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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“…Es konnte bereits gezeigt werden, dass selbst SNPs in großer Distanz, sogar auf anderen Chromosomen, mit Veränderungen der DNA-Methylierung und damit der Regulation von Genen assoziiert sind [33]. Für Adipositas konnte ein solcher Zusammenhang mit DNA-Methylierung für 28 SNPs gezeigt werden, die ursprünglich in GWAs identifiziert wurden [34]. Die systematischen Untersuchungen des gesamten "Epigenoms" stecken momentan noch in den Anfängen.…”

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Genomweite Assoziationsstudien zu Adipositas und was wir daraus lernen

Kronenberg

Paulweber²,

Lamina

2016

Wien Med Wochenschr

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The introduction of genome-wide association studies resulted in a tremendous increase in the number of genes associated with obesity and related phenotypes (BMI, waist and waist-hip-ratio). Despite this enormous gain in knowledge the search for genes is only started since only a small fraction of the heritability of these phenotypes is explained yet: each single gene of the 97 hitherto known BMI-associated genes and 49 waist-hip-ratio-associated genes explains only a tiny fraction of the variance of these phenotypes. Sex-specific differences are mainly known for waist-hip-ratio and ̴40% of the genes showed only an effect in women but no or a markedly smaller effect in men. The functional characterization of the identified genes will take a lot of time. It is unclear whether and how fast the findings will result in therapeutic consequences. It is of utmost importance that we understand the involved mechanisms before new therapeutic strategies can be developed.

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Many obesity-associated SNPs strongly associate with DNA methylation changes at proximal promoters and enhancers

Cited by 134 publications

References 84 publications

The importance of gene–environment interactions in human obesity

The importance of gene–environment interactions in human obesity

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

Genomweite Assoziationsstudien zu Adipositas und was wir daraus lernen

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