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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

Genotype at rs10948172 correlates with the methylation levels at four CpG sites located downstream of SUPT3H. (A) The plot shows the association between rs10948172 genotype and the methylation levels of CpG probes that are present within the LD block. The x-axis represents the genomic position of the CpG probes, and the y-axis represents the Benjamini–Hochberg corrected –log10P-value of the correlation between rs10948172 genotype and each CpG probe β-value. Each open circle represents a single CpG probe, the genomic location of rs10948172 is indicated by a bold dashed line, and the LD block is indicated by the vertical dotted lines. The location of the SUPT3H and RUNX2 genes is indicated by arrows. (B) The association between genotype at rs10948172 and methylation levels at the four significant CpG probes. Due to the significant methylation differences at these CpGs between OA and NOF samples, data are shown only for the 80 OA samples from the discovery cohort of 99 samples. The level of methylation at the CpG probes is shown as the β-value. Horizontal line represents the mean.
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DDV433F2: Genotype at rs10948172 correlates with the methylation levels at four CpG sites located downstream of SUPT3H. (A) The plot shows the association between rs10948172 genotype and the methylation levels of CpG probes that are present within the LD block. The x-axis represents the genomic position of the CpG probes, and the y-axis represents the Benjamini–Hochberg corrected –log10P-value of the correlation between rs10948172 genotype and each CpG probe β-value. Each open circle represents a single CpG probe, the genomic location of rs10948172 is indicated by a bold dashed line, and the LD block is indicated by the vertical dotted lines. The location of the SUPT3H and RUNX2 genes is indicated by arrows. (B) The association between genotype at rs10948172 and methylation levels at the four significant CpG probes. Due to the significant methylation differences at these CpGs between OA and NOF samples, data are shown only for the 80 OA samples from the discovery cohort of 99 samples. The level of methylation at the CpG probes is shown as the β-value. Horizontal line represents the mean.

Mentions: Genotype at the SUPT3H SNP rs10948172 correlated with the methylation of four adjacent CpGs located ∼82 kb upstream from the SNP: cg13979708, cg19254793, cg20913747 and cg18551225. All four are located within the LD region marked by rs10948172, which encompasses a ∼667 kb region from hg19 chromosome 6:44 683 049–45 349 877 (Fig. 2A). These four CpG sites are 650 kb downstream of the SUPT3H transcription start site (TSS) (Fig. 2A), and for each, the OA-associated G allele of rs10948172 correlated with lower methylation (Fig. 2B; data for the OA patients only shown). rs10948172 is associated with OA in males but not in females (11). However, the meQTL was operating in both males and females (Supplementary Material, Fig. S1), although there is reduced methylation of cg13979708, cg20913747 and cg18551225 in males independent of rs10948172 genotype (Supplementary Material, Fig. S1A, C and D). The meQTL was observed for all of the patient samples combined and in OA samples alone (Table 2).Figure 2.


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)

Genotype at rs10948172 correlates with the methylation levels at four CpG sites located downstream of SUPT3H. (A) The plot shows the association between rs10948172 genotype and the methylation levels of CpG probes that are present within the LD block. The x-axis represents the genomic position of the CpG probes, and the y-axis represents the Benjamini–Hochberg corrected –log10P-value of the correlation between rs10948172 genotype and each CpG probe β-value. Each open circle represents a single CpG probe, the genomic location of rs10948172 is indicated by a bold dashed line, and the LD block is indicated by the vertical dotted lines. The location of the SUPT3H and RUNX2 genes is indicated by arrows. (B) The association between genotype at rs10948172 and methylation levels at the four significant CpG probes. Due to the significant methylation differences at these CpGs between OA and NOF samples, data are shown only for the 80 OA samples from the discovery cohort of 99 samples. The level of methylation at the CpG probes is shown as the β-value. Horizontal line represents the mean.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

DDV433F2: Genotype at rs10948172 correlates with the methylation levels at four CpG sites located downstream of SUPT3H. (A) The plot shows the association between rs10948172 genotype and the methylation levels of CpG probes that are present within the LD block. The x-axis represents the genomic position of the CpG probes, and the y-axis represents the Benjamini–Hochberg corrected –log10P-value of the correlation between rs10948172 genotype and each CpG probe β-value. Each open circle represents a single CpG probe, the genomic location of rs10948172 is indicated by a bold dashed line, and the LD block is indicated by the vertical dotted lines. The location of the SUPT3H and RUNX2 genes is indicated by arrows. (B) The association between genotype at rs10948172 and methylation levels at the four significant CpG probes. Due to the significant methylation differences at these CpGs between OA and NOF samples, data are shown only for the 80 OA samples from the discovery cohort of 99 samples. The level of methylation at the CpG probes is shown as the β-value. Horizontal line represents the mean.
Mentions: Genotype at the SUPT3H SNP rs10948172 correlated with the methylation of four adjacent CpGs located ∼82 kb upstream from the SNP: cg13979708, cg19254793, cg20913747 and cg18551225. All four are located within the LD region marked by rs10948172, which encompasses a ∼667 kb region from hg19 chromosome 6:44 683 049–45 349 877 (Fig. 2A). These four CpG sites are 650 kb downstream of the SUPT3H transcription start site (TSS) (Fig. 2A), and for each, the OA-associated G allele of rs10948172 correlated with lower methylation (Fig. 2B; data for the OA patients only shown). rs10948172 is associated with OA in males but not in females (11). However, the meQTL was operating in both males and females (Supplementary Material, Fig. S1), although there is reduced methylation of cg13979708, cg20913747 and cg18551225 in males independent of rs10948172 genotype (Supplementary Material, Fig. S1A, C and D). The meQTL was observed for all of the patient samples combined and in OA samples alone (Table 2).Figure 2.

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