Osteoarthritis Susceptibility Locus Research Articles

Multi-tissue epigenetic analysis of the osteoarthritis susceptibility locus mapping to the plectin gene PLEC

SummaryObjectiveIn cartilage, the osteoarthritis (OA) associated single nucleotide polymorphism (SNP) rs11780978 correlates with differential expression of PLEC, and with differential methylation of PLEC CpG dinucleotides, forming eQTLs and mQTLs respectively. This implies that methylation links chondrocyte genotype and phenotype, thus driving the functional effect of this genetic risk signal. PLEC encodes plectin, a cytoskeletal protein that enables tissues to respond to mechanical forces. We sought to assess whether these PLEC functional effects were cartilage specific.MethodCartilage, fat pad, synovium and peripheral blood were collected from patients undergoing arthroplasty. PLEC CpGs were analysed for mQTLs and allelic expression imbalance (AEI) was performed to test for eQTLs. Plectin was knocked down in a mesenchymal stem cell (MSC) line using CRISPR/Cas9 and cells phenotyped by RNA-sequencing.ResultsmQTLs were discovered in fat pad, synovium and blood. Their effects were however stronger in the joint tissues and of comparable effect between these tissues. We observed AEI in synovium in the same direction as for cartilage and correlations between methylation and PLEC expression. Knocking-down plectin impacted on pathways reported to have a role in OA, including Wnt signalling, glycosaminoglycan biosynthesis and immune regulation.ConclusionsSynovium is also a target of the rs11780978 OA association functionally operating on PLEC. In fat pad, mQTLs were identified but these did not correlate with PLEC expression, suggesting the functional effect is not joint-wide. Our study highlights interplay between genetic risk, DNA methylation and gene expression in OA, and reveals clear differences between tissues from the same diseased joint.

Multi-tissue epigenetic analysis of the osteoarthritis susceptibility locus mapping to the plectin gene PLEC

Purpose: We previously demonstrated that genotype at the OA associated SNP rs11780978, which resides within an intron of PLEC, correlates with differential expression of this gene and with differential methylation of PLEC CG dinucleotides (CpGs). These genetic, transcriptomic and epigenetic analyses were undertaken on cartilage DNA and RNA, and implied that DNA methylation links chondrocyte genotype and phenotype, with this epigenetic mechanism driving the functional impact of the rs11780978 risk signal. PLEC encodes Plectin, a cytoskeletal protein that regulates signalling from the extracellular space to the nucleus. In so doing, Plectin enables cells to respond to external mechanical stimuli and maintain tissue integrity. PLEC is expressed widely and in this study, we set out to test whether the PLEC functional effects that we had discovered were cartilage specific or whether they were active in other joint or non-joint tissues. Methods: RNA and genomic DNA were extracted from cartilage (n=35), infrapatellar fat-pad (n=68), synovium (n=79) and peripheral whole blood (n=54) tissue samples from patients who had undergone hip or knee arthroplasty for OA. Allelic expression imbalance (AEI) at PLEC was assessed by pyrosequencing in individuals heterozygous for the PLEC transcript SNP rs11783799 (pairwise r2=0.93 relative to rs11780978). The AEI was performed on DNA (providing the 1:1 ratio of allelic balance) and cDNA synthesised from the tissue RNA. DNA ratios were compared to cDNA ratios and P-values were calculated using a Mann-Whitney 2-tailed exact test. Methylation analysis of PLEC CpGs was performed by bisulphite conversion of tissue DNA followed by pyrosequencing. Patients were stratified by rs11780978 genotype and methylation levels compared, with P-values calculated using the Kruskal-Wallis test. Results: We observed AEI in synovium (P=0.005) in the same direction as for cartilage, with decreased expression of PLEC correlating with the OA risk-conferring A allele of rs11780978. We did not observe AEI in fat pad (P>0.05) and were unable to test for it in blood due to low expression level of the gene as confirmed by qPCR. The CpG analysis focussed on our two previously reported PLEC CpG clusters; cg19405177 and 7 nearby CpGs (in a 112bp interval), and cg14598846 and 3 adjacent CpGs (in a 23bp interval). In cartilage DNA, we replicated the correlation between rs11780978 genotype and methylation at the cg19405177 cluster (risk-conferring A allele of rs11780978 correlating with increased methylation; P<0.01) and at the cg14598846 cluster (risk-conferring A allele of rs11780978 correlating with decreased methylation; P<0.0001). We observed the same effects and in the same directions for synovium (cg19405177 cluster, P<0.001; cg14598846 cluster, P<0.0001), fat pad (cg19405177 cluster, P<0.05; cg14598846 cluster, P<0.0001) and blood (cg19405177 cluster, P<0.001; cg14598846 cluster, P<0.0001) DNAs. We next created a heat-map displaying the percentage effect of rs11780978 genotype on CpG methylation at the two clusters (Figure 1). This confirmed the effect of genotype on methylation across the four tissue types but highlighted that the effects are strongest in the joint tissues. Conclusions: Our study has revealed that as for cartilage, synovium is a target of the OA association that is functionally operating on PLEC expression and methylation; we observed AEI and a correlation between rs11780978 genotype and methylation for this tissue. In fat pad, although we observed methylation correlations, there was no AEI. This suggests that the functional effect of the association signal is not joint-wide and that there is a difference in sensitivity to epigenetic regulation of PLEC between cartilage/synovium and fat pad. These distinctions point toward regulatory variability in PLEC expression mediated by the same association signal depending on tissue type. This was exemplified further by our analysis of blood, with very low levels of PLEC expression and with a much weaker effect of rs11780978 genotype on methylation. Our study highlights the interplay between OA genetic risk, DNA methylation and gene expression, but reveals clear differences in these effects even for tissues from the same diseased joint.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

A genome-wide association study in Japanese identified a new knee osteoarthritis susceptibility locus

A genome-wide association study in Japanese identified a new knee osteoarthritis susceptibility locus

Investigation of the Relationship Between Susceptibility Loci for Hip Osteoarthritis and Dual X-Ray Absorptiometry-Derived Hip Shape in a Population-Based Cohort of PerimenopausalWomen.

To examine relationships between known osteoarthritis (OA) susceptibility loci and hip shape in a population-based cohort of perimenopausal women in order to investigate whether hip shape contributes to OA development. Hip shape was measured, using statistical shape modeling, on dual x-ray absorptiometry scans of the hip from mothers in the Avon Longitudinal Study of Parents and Children (ALSPAC). The proximal femur and superior acetabulum were outlined, and independent hip shape modes were generated. In a subregional model, points were restricted to the acetabulum and superior femoral head. Associations between 11 OA-related single-nucleotide polymorphisms, identified by literature search, and shape modes were analyzed in a multivariate canonical correlation analysis. A total of 3,111 women (mean age 48 years) had genetic and hip shape data. The KLHDC5/PTHLH rs10492367 OA risk allele was associated with a wider upper femur in the whole shape model (P = 1 × 10-5 ). The DOT1L rs12982744 OA risk allele was associated with reduced superior joint space in the subregional shape model (P = 2 × 10-3 ). The COL11A1 rs4907986 OA risk allele was associated with lateral displacement of the femoral head relative to the acetabulum in the subregional shape model (P = 5 × 10-4 ). Regional association plots identified an additional COL11A1 locus in moderate linkage disequilibrium with rs4907986, which was more strongly associated with hip shape (rs10047217; P = 3 × 10-6 ). Colocalization analysis indicated sharing of genetic signals for hip shape and hip OA for the KLHDC5/PTHLH and COL11A1 loci. Hip OA susceptibility loci were associated with shape in this study, suggesting that these loci (and potentially yet-to-be-identified hip OA loci) could contribute to hip OA in later life via perturbing biologic pathways that mediate morphology development.

Association study of candidate genes for susceptibility to Kashin-Beck disease in a Tibetan population

BackgroundMany osteoarthritis (OA) susceptibility genes have been identified in recent years. Given the overlap in the phenotype of joint inflammation between OA and Kashin-Beck disease (KBD), the aim of this study is to explore whether the reported OA susceptibility genes and two genes that may link to OA pathophysiology are associated with KBD in the Tibetan population.MethodFifteen single-nucleotide polymorphisms (SNPs) in 12 candidate genes previously reported as OA susceptibility loci were selected for investigation. Genotyping was performed using the SNaPshot method for these SNPs in a Tibetan population composed of 849 KBD patients and 565 normal controls. Meanwhile, the coding regions of two genes, COL10A1 and HABP2, which may involve in the pathological mechanism of OA/KBD, were sequenced by Sanger sequencing to identify susceptibility coding variants for KBD in the Tibetan population.ResultsThe two arthritis-susceptible candidate SNPs, rs7775 (p.Arg324Gly) in the FRZB gene and rs7033979 in the ASPN gene, showed associations with KBD (OR = 1.568, P = 4 × 10−3 and OR = 0.744, P = 8 × 10−3, respectively). The coding variants rs142463796 (p.Asp128Asn) and rs2228547 (p.Gly545Arg) in the COL10A1 gene (OR = 9.832 and P = 6 × 10−3 and OR = 1.242, P = 0.043, respectively) and rs548354451 (p.Asp272Glu) in the HABP2 gene (OR = 2.813, P = 0.010) were associated with KBD patients.ConclusionThese finding suggested that rs7775 in the FRZB gene may increase susceptibility to KBD, while rs7033979 in the ASPN gene may play a protective role in susceptibility to KBD in Tibetans. Moreover, genetic variants in chondrogenesis-related genes COL10A1 and HABP2 may play a role in the risk of developing KBD in the Tibetan population.

Identification of five novel osteoarthritis susceptibility loci through the UK biobank resourse of five novel osteoarthritis susceptibility loci through the UK biobank resourse

Identification of five novel osteoarthritis susceptibility loci through the UK biobank resourse of five novel osteoarthritis susceptibility loci through the UK biobank resourse

Epigenetic and transcriptional effects operate on the SUPT3H and RUNX2 genes residing at the chromosome 6p21.1 osteoarthritis susceptibility locus and correlate with the association signal

Epigenetic and transcriptional effects operate on the SUPT3H and RUNX2 genes residing at the chromosome 6p21.1 osteoarthritis susceptibility locus and correlate with the association signal

DNA methylation modulated by the osteoarthritis susceptibility locus marked by rs6094710 is associated with regulation of NCOA3 gene expression

DNA methylation modulated by the osteoarthritis susceptibility locus marked by rs6094710 is associated with regulation of NCOA3 gene expression

Genetic association studies in osteoarthritis: is it fairytale?

Osteoarthritis is a common complex disorder with a strong genetic component. Other identified risk factors such as increasing age and overweight do not fully explain the risk of osteoarthritis. Here, we highlight the main findings from genetic association studies on osteoarthritis to date. Currently, genetic association studies have identified 21 independent susceptibility loci for osteoarthritis. Studies have focused on hip, knee and hand osteoarthritis, as well as posttotal joint replacement and minimum joint space width, a proxy for cartilage thickness. Four distinct loci have recently been identified in a genome-wide association scan on minimum joint space width. The role of mitochondrial DNA variants has been the focus of a recent meta-analysis. Findings have previously been mixed, however, this study suggests a plausible involvement of mitochondrial DNA in the progression of radiographic knee osteoarthritis. Identifying genetic locations of interest provides a framework upon which to base future studies, for example replication analysis and functional work. Genetic association studies have shaped and will continue to shape research in this field. Improving the understanding of osteoarthritis could improve the diagnosis and treatment of the disease and improve quality of life for many individuals.

Expression analysis of the osteoarthritis genetic susceptibility locus mapping to an intron of the MCF2L gene and marked by the polymorphism rs11842874

Background: Osteoarthritis (OA) is a painful, debilitating disease characterised by loss of articular cartilage with concurrent changes in other tissues of the synovial joint. Genetic association studies have shown that a number of common variants increase the risk of developing OA. Investigating their activity can uncover novel causal pathways and potentially highlight new treatment targets. One of the reported OA association signals is marked by the single nucleotide polymorphism (SNP) rs11842874 at chromosome 13q34. rs11842874 is positioned within a small linkage disequilibrium (LD) block within intron 4 of MCF2L, a gene encoding guanine-nucleotide exchange factor DBS. There are no non-synonymous SNPs that correlate with this association signal and we therefore set out to assess whether its effect on OA susceptibility is mediated by alteration of MCF2L expression. Methods: Nucleic acid was extracted from cartilage, synovial membrane or infrapatellar fat pad tissues from OA patients. Expression of MCF2L was measured by quantitative PCR and RNA-sequencing whilst the presence of DBS was studied using immunohistochemistry. The functional effect of SNPs within the 13q34 locus was assessed using public databases and in vitro using luciferase reporter analysis. Results: MCF2L gene and protein expression are detectable in joint tissues, with quantitative differences in the expression of the gene and in the transcript isoforms expressed between the tissues tested. There is an expression quantitative trait locus (eQTL) operating within synovial membrane tissue, with possession of the risk-conferring A allele of rs11842874 correlating with increased MCF2L expression. SNPs within the rs11842874 LD block reside within transcriptional regulatory elements and their direct analysis reveals that several show quantitative differences in regulatory activity at the allelic level. Conclusions: MCF2L is subject to a cis-acting eQTL in synovial membrane that correlates with the OA association signal. This signal contains several functional SNPs that could account for the susceptibility and which therefore merit further investigation. As far as we are aware, this is the first example of an OA susceptibility locus operating as an eQTL in synovial membrane tissue but not in cartilage.

Expression analysis of the osteoarthritis genetic susceptibility locus mapping to an intron of the MCF2L gene and marked by the polymorphism rs11842874.

BackgroundOsteoarthritis (OA) is a painful, debilitating disease characterised by loss of articular cartilage with concurrent changes in other tissues of the synovial joint. Genetic association studies have shown that a number of common variants increase the risk of developing OA. Investigating their activity can uncover novel causal pathways and potentially highlight new treatment targets. One of the reported OA association signals is marked by the single nucleotide polymorphism (SNP) rs11842874 at chromosome 13q34. rs11842874 is positioned within a small linkage disequilibrium (LD) block within intron 4 of MCF2L, a gene encoding guanine-nucleotide exchange factor DBS. There are no non-synonymous SNPs that correlate with this association signal and we therefore set out to assess whether its effect on OA susceptibility is mediated by alteration of MCF2L expression.MethodsNucleic acid was extracted from cartilage, synovial membrane or infrapatellar fat pad tissues from OA patients. Expression of MCF2L was measured by quantitative PCR and RNA-sequencing whilst the presence of DBS was studied using immunohistochemistry. The functional effect of SNPs within the 13q34 locus was assessed using public databases and in vitro using luciferase reporter analysis.ResultsMCF2L gene and protein expression are detectable in joint tissues, with quantitative differences in the expression of the gene and in the transcript isoforms expressed between the tissues tested. There is an expression quantitative trait locus (eQTL) operating within synovial membrane tissue, with possession of the risk-conferring A allele of rs11842874 correlating with increased MCF2L expression. SNPs within the rs11842874 LD block reside within transcriptional regulatory elements and their direct analysis reveals that several show quantitative differences in regulatory activity at the allelic level.ConclusionsMCF2L is subject to a cis-acting eQTL in synovial membrane that correlates with the OA association signal. This signal contains several functional SNPs that could account for the susceptibility and which therefore merit further investigation. As far as we are aware, this is the first example of an OA susceptibility locus operating as an eQTL in synovial membrane tissue but not in cartilage.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0254-2) contains supplementary material, which is available to authorized users.

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

Osteoarthritis (OA) is a common, painful and debilitating disease of articulating joints resulting from the age-associated loss of cartilage. Well-powered genetic studies have identified a number of DNA polymorphisms that are associated with OA susceptibility. Like most complex trait loci, these OA loci are thought to influence disease susceptibility through the regulation of gene expression, so-called expression quantitative loci, or eQTLs. One mechanism through which eQTLs act is epigenetic, by modulating DNA methylation. In such cases, there are quantitative differences in DNA methylation between the two alleles of the causal polymorphism, with the association signal referred to as a methylation quantitative trait locus, or meQTL. In this study, we aimed to investigate whether the OA susceptibility loci identified to date are functioning as meQTLs by integrating genotype data with whole genome methylation data of cartilage DNA. 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. Three of these replicated in an additional cohort of up to 62 OA patients. 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.

Functional characterisation of the osteoarthritis susceptibility locus at chromosome 6q14.1 marked by the polymorphism rs9350591.

BackgroundThe arcOGEN genome-wide association study reported the rs9350591 C/T single nucleotide polymorphism (SNP) as marking a region on chromosome 6q14.1 that is associated with hip osteoarthritis (OA) in Europeans, with an odds ratio (OR) of 1.18 and a p-value of 2.42 × 10−9. rs9350591 is an intergenic SNP surrounded by seven genes within 1 Mb. Six of the genes are expressed in cartilage. We sought to characterise this signal to assess whether the association of rs9350591 with OA is mediated by modulating gene expression.MethodsTotal RNA was extracted from hip or knee cartilage of 161 OA patients and from hip cartilage of 29 non-OA patients who had undergone hip replacements as a result of neck-of-femur (NOF) fractures. We used quantitative PCR (qPCR) to measure overall gene expression, and pyrosequencing to assess allelic expression of the genes. A mesenchymal stem cell (MSC) differentiation model was used to assess gene expression during chondrogenesis.ResultsWe identified a significant decrease in the expression of SENP6 (p = 0.005) and MYO6 (p = 0.026) in OA hip cartilage relative to the non-OA hip control cartilage. However, we found no evidence for a correlation between gene expression and rs9350591 genotype for any of the six genes. In addition, we identified expression quantitative trait loci (eQTLs) operating on COL12A1, TMEM30A, SENP6 and MYO6, although these were not relevant to the OA associated signal. Finally, all genes were dynamically expressed during chondrogenesis.ConclusionsThe regulation of gene expression at this locus is complex, highlighted by the down-regulation of SENP6 and MYO6 in OA hip cartilage and by eQTLs operating on four of the genes at the locus. However, modulation of gene expression in the end-stage OA cartilage that we have investigated is not the mechanism by which this association signal is operating. As implied by the dynamic patterns of gene expression throughout chondrogenesis, the association signal marked by rs9350591 could instead be exerting its effects during joint development.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0215-9) contains supplementary material, which is available to authorized users.

Investigation of association between hip osteoarthritis susceptibility loci and radiographic proximal femur shape.

ObjectiveTo test whether previously reported hip morphology or osteoarthritis (OA) susceptibility loci are associated with proximal femur shape as represented by statistical shape model (SSM) modes and as univariate or multivariate quantitative traits.MethodsWe used pelvic radiographs and genotype data from 929 subjects with unilateral hip OA who had been recruited previously for the Arthritis Research UK Osteoarthritis Genetics Consortium genome‐wide association study. We built 3 SSMs capturing the shape variation of the OA‐unaffected proximal femur in the entire mixed‐sex cohort and for male/female‐stratified cohorts. We selected 41 candidate single‐nucleotide polymorphisms (SNPs) previously reported as being associated with hip morphology (for replication analysis) or OA (for discovery analysis) and for which genotype data were available. We performed 2 types of analysis for genotype–phenotype associations between these SNPs and the modes of the SSMs: 1) a univariate analysis using individual SSM modes and 2) a multivariate analysis using combinations of SSM modes.ResultsThe univariate analysis identified association between rs4836732 (within the ASTN2 gene) and mode 5 of the female SSM (P = 0.0016) and between rs6976 (within the GLT8D1 gene) and mode 7 of the mixed‐sex SSM (P = 0.0003). The multivariate analysis identified association between rs5009270 (near the IFRD1 gene) and a combination of modes 3, 4, and 9 of the mixed‐sex SSM (P = 0.0004). Evidence of associations remained significant following adjustment for multiple testing. All 3 SNPs had previously been associated with hip OA.ConclusionThese de novo findings suggest that rs4836732, rs6976, and rs5009270 may contribute to hip OA susceptibility by altering proximal femur shape.

Genetic contribution to osteoarthritis development

Purpose of reviewPowerful association studies have identified a number of genetic signals that can be confidently judged as associated with osteoarthritis. Efforts have continued to discover new loci, whilst functional studies are being applied to assess which genes are the likely targets of the risk-conferring alleles. The study of epigenetics has highlighted an interaction between osteoarthritis genetics and DNA methylation. This review will summarize some of the recent key studies in osteoarthritis genetics, including functional and epigenetic analyses.Recent findingsSeveral novel osteoarthritis susceptibility loci have been reported recently, including the regulatory genes NCOA3 and ALDH1A2. Functional analyses of these genes and of others reported previously support earlier suggestions that osteoarthritis susceptibility is principally mediated by modulations to gene expression. DNA methylation analyses provide additional insights into the osteoarthritis disease process, at both a genome-wide level and when investigating direct interactions with risk-conferring alleles.SummaryOsteoarthritis genetic risk predominantly acts by modulating gene expression, an effect typically mediated via transcriptional regulation. Effects on various pathways have been detected, including cell differentiation and cartilage homeostasis. The continued identification of risk loci, their functional study, and the unification of genetic and epigenetic analyses will be key themes in the future.

Adult mice lacking the type 2 iodothyronine deiodinase have increased subchondral bone but normal articular cartilage.

Although osteoarthritis (OA) is the commonest joint disorder and has a rising prevalence as the population ages, no drugs are available that prevent or delay the onset and progression of disease. Recent studies identified the DIO2 gene encoding type 2 deiodinase (D2) as a susceptibility locus for OA, and further data suggest deiodinase-regulated local availability of triiodothyronine (T3) in the joint plays an important role in cartilage maintenance and repair. To investigate the hypothesis that reduced tissue T3 availability protects joints from development of OA, the joint phenotypes of adult mice lacking D2 (D2KO) or lacking both D1 and D2 (D1D2KO), the only enzymes that catalyze conversion of the prohormone thyroxine to active T3, were determined. Knee joints were prepared from male 16-week-old adult wild type (WT; n=9), D2KO (n=5), and D1D2KO (n=3) mice. Articular cartilage pathology was scored using the Osteoarthritis Research Society International (OARSI) histopathology scale for murine OA to determine the severity and extent of disease. Digital X-ray microradiography was used to determine the area and mineral content of subchondral bone immediately beneath the articular cartilage surface. There were no differences in maximum and standardized OA scores, cartilage erosion indices, or articular cartilage cellularity among WT, D2KO, and D1D2KO mice. Subchondral bone area did not differ among genotypes, but mineral content was markedly increased in both D2KO and D1D2KO mice compared to WT. Although adult D2KO mice have normal articular cartilage and no other features of spontaneous joint damage, they exhibit increased subchondral bone mineral content.

Allelic expression analysis of the osteoarthritis susceptibility locus that maps to chromosome 3p21 reveals cis-acting eQTLs at GNL3 and SPCS1.

BackgroundAn osteoarthritis (OA) susceptibility locus has been mapped to chromosome 3p21, to a region of high linkage disequilibrium encompassing twelve genes. Six of these genes are expressed in joint tissues and we therefore assessed whether any of the six were subject to cis-acting regulatory polymorphisms active in these tissues and which could therefore account for the association signal.MethodsWe measured allelic expression using pyrosequencing assays that can distinguish mRNA output from each allele of a transcript single nucleotide polymorphism. We assessed RNA extracted from the cartilage and other joint tissues of OA patients who had undergone elective joint replacement surgery. A two-tailed Mann–Whitney exact test was used to test the significance of any allelic differences.ResultsGNL3 and SPCS1 demonstrated significant allelic expression imbalance (AEI) in OA cartilage (GNL3, mean AEI = 1.04, p = 0.0002; SPCS1, mean AEI = 1.07, p < 0.0001). Similar results were observed in other tissues. Expression of the OA-associated allele was lower than that of the non-associated allele for both genes.Conclusionscis-acting regulatory polymorphisms acting on GNL3 and SPCS1 contribute to the OA association signal at chromosome 3p21, and these genes therefore merit further investigation.

Allelic expression analysis of genes from within the osteoarthritis susceptibility locus at chromosome 3p21 reveals functional gene expression effects at GNL3 and SPCS1 that correlate with the association signal

Allelic expression analysis of genes from within the osteoarthritis susceptibility locus at chromosome 3p21 reveals functional gene expression effects at GNL3 and SPCS1 that correlate with the association signal

Functional analysis of the osteoarthritis susceptibility locus marked by the polymorphism rs10492367

Functional analysis of the osteoarthritis susceptibility locus marked by the polymorphism rs10492367

Powerful detection of osteoarthritis susceptibility loci by comprehensive examination of clinically important endophenotypes

1 PI3K Akt signaling pathway 337 21 2.96E-08 -5.30E+01 1.20E-02 8.09E-09 7.93E-07 7.93E-07 Inhibited 2 Circadian rhythm 30 7 2.04E-07 -7.24E+00 5.00E-02 1.98E-07 9.70E-06 1.94E-05 Inhibited 3 HIF-1-alpha transcription factor network 63 10 2.50E-08 1.55E+00 6.68E-01 3.16E-07 3.59E-05 4.49E-05 Activated 4 Validated transcriptional targets of AP1 family members Fra1 and Fra2 37 7 9.46E-07 6.56E+00 2.90E-02 5.05E-07 3.59E-05 7.17E-05 Activated