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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

Replication of the association between rs10948172 and DNA methylation. (A–G) Graphs show the association between genotype at rs10948172 and the methylation levels at seven CpGs measured by pyrosequencing; the four discovery CpGs (B, cg13979708; C, cg19254793; D, cg20913747 and E, cg18551225) and the three additional CpG sites captured by the assays located (A) 3 bp upstream of cg13979708, (F) 7 bp downstream of cg18551225 and (G) 11 bp downstream of cg18551225. Data are shown for the 57 OA samples studied. P-value was calculated using a Kruskal–Wallis test and was Bonferroni-corrected for multiple testing. Horizontal line represents the mean.
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DDV433F5: Replication of the association between rs10948172 and DNA methylation. (A–G) Graphs show the association between genotype at rs10948172 and the methylation levels at seven CpGs measured by pyrosequencing; the four discovery CpGs (B, cg13979708; C, cg19254793; D, cg20913747 and E, cg18551225) and the three additional CpG sites captured by the assays located (A) 3 bp upstream of cg13979708, (F) 7 bp downstream of cg18551225 and (G) 11 bp downstream of cg18551225. Data are shown for the 57 OA samples studied. P-value was calculated using a Kruskal–Wallis test and was Bonferroni-corrected for multiple testing. Horizontal line represents the mean.

Mentions: All four discovery CpGs within the rs10948172 SUPT3H meQTL region replicated in the additional cohort, with the OA-associated G allele again correlating with lower methylation (Fig. 5B–E). Additionally, three further CpG sites were captured by the pyrosequencing assays, the first located 3 bp upstream of cg13979708, and the other two located 7 and 11 bp downstream of cg18551225. All three additional CpG sites demonstrated significant correlation between rs10948172 genotype and methylation (Fig. 5A, F and G), and in the same direction as that seen for the four discovery CpGs. This replication analysis of rs10948172 included an additional 17 OA knee patient samples (Supplementary Material, Table S1) that were included to enhance our power to detect any gender differences in methylation independently of genotype at this male-specific susceptibility locus, making a total of 57 OA patient samples (34 females and 23 males). As with the discovery cohort, the effect of rs10948172 genotype on methylation of the seven CpG sites within the meQTL region was observed in both males and females (data not shown), even though the OA genetic risk at this locus is male specific.Figure 5.


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)

Replication of the association between rs10948172 and DNA methylation. (A–G) Graphs show the association between genotype at rs10948172 and the methylation levels at seven CpGs measured by pyrosequencing; the four discovery CpGs (B, cg13979708; C, cg19254793; D, cg20913747 and E, cg18551225) and the three additional CpG sites captured by the assays located (A) 3 bp upstream of cg13979708, (F) 7 bp downstream of cg18551225 and (G) 11 bp downstream of cg18551225. Data are shown for the 57 OA samples studied. P-value was calculated using a Kruskal–Wallis test and was Bonferroni-corrected for multiple testing. Horizontal line represents the mean.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

DDV433F5: Replication of the association between rs10948172 and DNA methylation. (A–G) Graphs show the association between genotype at rs10948172 and the methylation levels at seven CpGs measured by pyrosequencing; the four discovery CpGs (B, cg13979708; C, cg19254793; D, cg20913747 and E, cg18551225) and the three additional CpG sites captured by the assays located (A) 3 bp upstream of cg13979708, (F) 7 bp downstream of cg18551225 and (G) 11 bp downstream of cg18551225. Data are shown for the 57 OA samples studied. P-value was calculated using a Kruskal–Wallis test and was Bonferroni-corrected for multiple testing. Horizontal line represents the mean.
Mentions: All four discovery CpGs within the rs10948172 SUPT3H meQTL region replicated in the additional cohort, with the OA-associated G allele again correlating with lower methylation (Fig. 5B–E). Additionally, three further CpG sites were captured by the pyrosequencing assays, the first located 3 bp upstream of cg13979708, and the other two located 7 and 11 bp downstream of cg18551225. All three additional CpG sites demonstrated significant correlation between rs10948172 genotype and methylation (Fig. 5A, F and G), and in the same direction as that seen for the four discovery CpGs. This replication analysis of rs10948172 included an additional 17 OA knee patient samples (Supplementary Material, Table S1) that were included to enhance our power to detect any gender differences in methylation independently of genotype at this male-specific susceptibility locus, making a total of 57 OA patient samples (34 females and 23 males). As with the discovery cohort, the effect of rs10948172 genotype on methylation of the seven CpG sites within the meQTL region was observed in both males and females (data not shown), even though the OA genetic risk at this locus is male specific.Figure 5.

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