Genome-wide association and functional studies identify theDOT1Lgene to be involved in cartilage thickness and hip osteoarthritis

Abstract

Hip osteoarthritis (HOA) is one of the most disabling and common joint disorders with a large genetic component that is, however, still ill-defined. To date, genome-wide association studies (GWAS) in osteoarthritis (OA) and specifically in HOA have yielded only few loci, which is partly explained by heterogeneity in the OA definition. Therefore, we here focused on radiographically measured joint-space width (JSW), a proxy for cartilage thickness and an important underlying intermediate trait for HOA. In a GWAS of 6,523 individuals on hip-JSW, we identified the G allele of rs12982744 on chromosome 19p13.3 to be associated with a 5% larger JSW ( P = 4.8 × 10 −10 ). The association was replicated in 4,442 individuals from three United Kingdom cohorts with an overall meta-analysis P value of 1.1 × 10 −11 . The SNP was also strongly associated with a 12% reduced risk for HOA ( P = 1 × 10 −4 ). The SNP is located in the DOT1L gene, which is an evolutionarily conserved histone methyltransferase, recently identified as a potentially dedicated enzyme for Wnt target-gene activation in leukemia. Immunohistochemical staining of the DOT1L protein in mouse limbs supports a role for DOT1L in chondrogenic differentiation and adult articular cartilage. DOT1L is also expressed in OA articular chondrocytes. Silencing of Dot1l inhibited chondrogenesis in vitro. Dot1l knockdown reduces proteoglycan and collagen content, and mineralization during chondrogenesis. In the ATDC5 chondrogenesis model system, DOT1L interacts with TCF and Wnt signaling. These data are a further step to better understand the role of Wnt-signaling during chondrogenesis and cartilage homeostasis. DOT1L may represent a therapeutic target for OA.

Osteoarthritis and bone mineral density: are strong bones bad for joints?

“…74 For example, a variant allele in the DOT1L gene has been associated with increased cartilage thickness (measured as joint space width) and a decreased risk of hip OA. 75 Another wnt pathway SNP has been found to influence hip morphology in women, and to modify the association between a particular morphological variant and radiographic hip OA. 76 Finally, bone-active OA susceptibility genes might be expected to directly increase the risk of developing phenotypes of OA characterised by bony features as a result of their effects on osteophyte formation and subchondral sclerosis.…”

DOT1L-Mediated H3K79 Methylation in Chromatin Is Dispensable for Wnt Pathway-Specific and Other Intestinal Epithelial Functions

“…Depletion of dDot1 or AF10 in Drosophila embryos re-duced expression of canonical Wnt targets, especially the highthreshold target senseless (30). Lastly, a human DOT1L polymorphism is associated with joint space width and reduced risk of osteoarthritis, and DOT1L knockdown in articular chondrocytes inhibited Wnt-dependent chondrogenesis (31). Each of these studies had certain limitations.…”

SWGDT: A sliding window-based genotype dependence testing tool for genome-wide susceptibility gene scan

“…Detailed description of experimental design and statistical analysis can be found in our previous studies [4]. Besides ITPR2 achieving genome-wide significant level in the GWAS of KBD, we further compared the GWAS results of KBD with that of 6 previous GWAS of OA [11][12][13][14][15][16]. 3 well known OA susceptibility genes also showed association signals in the GWAS of KBD, including CHST11 at 12q23 (P value = 7.88 Â 10 À4 at rs11112182), FILIP1 at 6q14 (P value = 0.009 at rs9293999) and SENP6 at 6q13 (P value = 0.010 at rs9352237).…”