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Methylation quantitative trait locus analysis of osteoarthritis links epigenetics with genetic risk.

Rushton MD, Reynard LN, Young DA, Shepherd C, Aubourg G, Gee F, Darlay R, Deehan D, Cordell HJ, Loughlin J - Hum. Mol. Genet. (2015)

Bottom Line: Well-powered genetic studies have identified a number of DNA polymorphisms that are associated with OA susceptibility.We investigated potential genotype-methylation correlations within a 1.0-1.5 Mb region surrounding each of 16 OA-associated single-nucleotide polymorphisms (SNPs) in 99 cartilage samples and identified four that function as meQTLs.These observations suggest that OA susceptibility loci regulate the level of DNA methylation in cis and provide a mechanistic explanation as to how these loci impact upon OA susceptibility, further increasing our understanding of the role of genetics and epigenetics in this common disease.

View Article: PubMed Central - PubMed

Affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine and.

No MeSH data available.


Related in: MedlinePlus

Genotypes at rs3204689 and rs143383 (rs6087704*) correlate with the methylation levels of the cg12031962 and cg14752227 CpG sites, respectively. (A). (C) Plots show the association between the OA-associated SNP and the methylation levels of CpG probes that are present within each LD block for that SNP. The genomic position of the CpG probes analysed is plotted on the x-axis, and the Benjamini–Hochberg corrected –log10P-value of the correlation between the genotype and the CpG probe β-value plotted on the y-axis. Each open circle represents a single CpG probe, and the significant associations are indicated. The genomic location of the OA-associated SNP is indicated by the bold dashed line, and the LD block is indicated by the vertical dotted lines. The genes within the region analysed are indicated below the association plot by arrows. (B), (D) Graphs of the association between genotype and methylation β-values for (B) rs3204689-cg12031962 and (D) rs143383-cg14752227. For rs3204689 and rs143383, data are shown for all 99 samples. Horizontal line represents the mean. *rs143383 is not present on the HumanOmniExpress genotyping array and rs6087704, an array SNP that has the highest LD with rs143383 (r2 = 0.93), was therefore used to infer rs143383 genotypes.
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DDV433F3: Genotypes at rs3204689 and rs143383 (rs6087704*) correlate with the methylation levels of the cg12031962 and cg14752227 CpG sites, respectively. (A). (C) Plots show the association between the OA-associated SNP and the methylation levels of CpG probes that are present within each LD block for that SNP. The genomic position of the CpG probes analysed is plotted on the x-axis, and the Benjamini–Hochberg corrected –log10P-value of the correlation between the genotype and the CpG probe β-value plotted on the y-axis. Each open circle represents a single CpG probe, and the significant associations are indicated. The genomic location of the OA-associated SNP is indicated by the bold dashed line, and the LD block is indicated by the vertical dotted lines. The genes within the region analysed are indicated below the association plot by arrows. (B), (D) Graphs of the association between genotype and methylation β-values for (B) rs3204689-cg12031962 and (D) rs143383-cg14752227. For rs3204689 and rs143383, data are shown for all 99 samples. Horizontal line represents the mean. *rs143383 is not present on the HumanOmniExpress genotyping array and rs6087704, an array SNP that has the highest LD with rs143383 (r2 = 0.93), was therefore used to infer rs143383 genotypes.

Mentions: The OA-associated C allele of the ALDH1A2 SNP rs3204689 correlated with lower methylation at the CpG cg12031962, which is located 107 kb from the SNP (Fig. 3A). This CpG is within the gene body of ALDH1A2 and within the OA susceptibility region. This meQTL was observed when all of the patient samples were combined (Fig. 3B) and in OA samples only (Table 2).Figure 3.


Methylation quantitative trait locus analysis of osteoarthritis links epigenetics with genetic risk.

Rushton MD, Reynard LN, Young DA, Shepherd C, Aubourg G, Gee F, Darlay R, Deehan D, Cordell HJ, Loughlin J - Hum. Mol. Genet. (2015)

Genotypes at rs3204689 and rs143383 (rs6087704*) correlate with the methylation levels of the cg12031962 and cg14752227 CpG sites, respectively. (A). (C) Plots show the association between the OA-associated SNP and the methylation levels of CpG probes that are present within each LD block for that SNP. The genomic position of the CpG probes analysed is plotted on the x-axis, and the Benjamini–Hochberg corrected –log10P-value of the correlation between the genotype and the CpG probe β-value plotted on the y-axis. Each open circle represents a single CpG probe, and the significant associations are indicated. The genomic location of the OA-associated SNP is indicated by the bold dashed line, and the LD block is indicated by the vertical dotted lines. The genes within the region analysed are indicated below the association plot by arrows. (B), (D) Graphs of the association between genotype and methylation β-values for (B) rs3204689-cg12031962 and (D) rs143383-cg14752227. For rs3204689 and rs143383, data are shown for all 99 samples. Horizontal line represents the mean. *rs143383 is not present on the HumanOmniExpress genotyping array and rs6087704, an array SNP that has the highest LD with rs143383 (r2 = 0.93), was therefore used to infer rs143383 genotypes.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664171&req=5

DDV433F3: Genotypes at rs3204689 and rs143383 (rs6087704*) correlate with the methylation levels of the cg12031962 and cg14752227 CpG sites, respectively. (A). (C) Plots show the association between the OA-associated SNP and the methylation levels of CpG probes that are present within each LD block for that SNP. The genomic position of the CpG probes analysed is plotted on the x-axis, and the Benjamini–Hochberg corrected –log10P-value of the correlation between the genotype and the CpG probe β-value plotted on the y-axis. Each open circle represents a single CpG probe, and the significant associations are indicated. The genomic location of the OA-associated SNP is indicated by the bold dashed line, and the LD block is indicated by the vertical dotted lines. The genes within the region analysed are indicated below the association plot by arrows. (B), (D) Graphs of the association between genotype and methylation β-values for (B) rs3204689-cg12031962 and (D) rs143383-cg14752227. For rs3204689 and rs143383, data are shown for all 99 samples. Horizontal line represents the mean. *rs143383 is not present on the HumanOmniExpress genotyping array and rs6087704, an array SNP that has the highest LD with rs143383 (r2 = 0.93), was therefore used to infer rs143383 genotypes.
Mentions: The OA-associated C allele of the ALDH1A2 SNP rs3204689 correlated with lower methylation at the CpG cg12031962, which is located 107 kb from the SNP (Fig. 3A). This CpG is within the gene body of ALDH1A2 and within the OA susceptibility region. This meQTL was observed when all of the patient samples were combined (Fig. 3B) and in OA samples only (Table 2).Figure 3.

Bottom Line: Well-powered genetic studies have identified a number of DNA polymorphisms that are associated with OA susceptibility.We investigated potential genotype-methylation correlations within a 1.0-1.5 Mb region surrounding each of 16 OA-associated single-nucleotide polymorphisms (SNPs) in 99 cartilage samples and identified four that function as meQTLs.These observations suggest that OA susceptibility loci regulate the level of DNA methylation in cis and provide a mechanistic explanation as to how these loci impact upon OA susceptibility, further increasing our understanding of the role of genetics and epigenetics in this common disease.

View Article: PubMed Central - PubMed

Affiliation: Musculoskeletal Research Group, Institute of Cellular Medicine and.

No MeSH data available.


Related in: MedlinePlus