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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

meQTL analysis of rs10948172-cg20913747 and rs3204689-cg12031962 in whole blood, synovium and fat pad from OA knee patients. (A) Methylation at cg20913747 stratified by genotype at the SUPT3H/RUNX2 OA SNP rs10948172. (B) Methylation at cg12031962 stratified by genotype at the ALDH1A2 OA SNP rs3204689. The 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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DDV433F8: meQTL analysis of rs10948172-cg20913747 and rs3204689-cg12031962 in whole blood, synovium and fat pad from OA knee patients. (A) Methylation at cg20913747 stratified by genotype at the SUPT3H/RUNX2 OA SNP rs10948172. (B) Methylation at cg12031962 stratified by genotype at the ALDH1A2 OA SNP rs3204689. The P-value was calculated using a Kruskal–Wallis test and was Bonferroni-corrected for multiple testing. Horizontal line represents the mean.

Mentions: For the SUPT3H/RUNX2 rs10948172 meQTL, we investigated the CpG cg20913747, which is subject to an rs10948172 meQTL in seven tissues in the published reports (Table 3). Furthermore, this CpG site showed the most significant effects in our cartilage data (Figs 2B and 5D), with genotype accounting for 27.8 and 24.6% of the total inter-individual variability in cg20913747 methylation in the discovery and replication cohorts, respectively. Although overall methylation was lower in synovium and fat pad than in cartilage, we observed a significant effect of rs10948172 genotype on cg20913747 methylation in all three tissue types in the same direction as in cartilage (Fig. 8A); rs10948172 genotype accounted for 63.1, 14.1 and 6.7% of cg20913747 methylation variability in synovium, fat pad and blood, respectively. For synovium and fat pad, this meQTL was independent of gender (Supplementary Material, Fig. S4B), although we observed a reduction in fat pad methylation in males relative to females that was independent of genotype (P = 0.009; Supplementary Material, Fig. S4). There is a non-significant decrease in methylation of cg20913747 in whole blood from males (Supplementary Material, Fig. S4A), and the effect of rs10948172 genotype on methylation appears to be male specific in this tissue (Supplementary Material, Fig. S4B). This, combined with the small effect size observed in blood relative to synovium and fat pad, may explain why this meQTL was not identified in other studies of whole blood (31,32).Figure 8.


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)

meQTL analysis of rs10948172-cg20913747 and rs3204689-cg12031962 in whole blood, synovium and fat pad from OA knee patients. (A) Methylation at cg20913747 stratified by genotype at the SUPT3H/RUNX2 OA SNP rs10948172. (B) Methylation at cg12031962 stratified by genotype at the ALDH1A2 OA SNP rs3204689. The 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

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

DDV433F8: meQTL analysis of rs10948172-cg20913747 and rs3204689-cg12031962 in whole blood, synovium and fat pad from OA knee patients. (A) Methylation at cg20913747 stratified by genotype at the SUPT3H/RUNX2 OA SNP rs10948172. (B) Methylation at cg12031962 stratified by genotype at the ALDH1A2 OA SNP rs3204689. The P-value was calculated using a Kruskal–Wallis test and was Bonferroni-corrected for multiple testing. Horizontal line represents the mean.
Mentions: For the SUPT3H/RUNX2 rs10948172 meQTL, we investigated the CpG cg20913747, which is subject to an rs10948172 meQTL in seven tissues in the published reports (Table 3). Furthermore, this CpG site showed the most significant effects in our cartilage data (Figs 2B and 5D), with genotype accounting for 27.8 and 24.6% of the total inter-individual variability in cg20913747 methylation in the discovery and replication cohorts, respectively. Although overall methylation was lower in synovium and fat pad than in cartilage, we observed a significant effect of rs10948172 genotype on cg20913747 methylation in all three tissue types in the same direction as in cartilage (Fig. 8A); rs10948172 genotype accounted for 63.1, 14.1 and 6.7% of cg20913747 methylation variability in synovium, fat pad and blood, respectively. For synovium and fat pad, this meQTL was independent of gender (Supplementary Material, Fig. S4B), although we observed a reduction in fat pad methylation in males relative to females that was independent of genotype (P = 0.009; Supplementary Material, Fig. S4). There is a non-significant decrease in methylation of cg20913747 in whole blood from males (Supplementary Material, Fig. S4A), and the effect of rs10948172 genotype on methylation appears to be male specific in this tissue (Supplementary Material, Fig. S4B). This, combined with the small effect size observed in blood relative to synovium and fat pad, may explain why this meQTL was not identified in other studies of whole blood (31,32).Figure 8.

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