Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A/B

Background: Canine osteosarcoma is clinically nearly identical to the human disease, but is common and highly heritable, making genetic dissection feasible. Results: Through genome-wide association analyses in three breeds (greyhounds, Rottweilers, and Irish wolfhounds), we identify 33 inherited risk loci explaining 55% to 85% of phenotype variance in each breed. The greyhound locus exhibiting the strongest association, located 150 kilobases upstream of the genes CDKN2A/B, is also the most rearranged locus in canine osteosarcoma tumors. The top germline candidate variant is found at a >90% frequency in Rottweilers and Irish wolfhounds, and alters an evolutionarily constrained element that we show has strong enhancer activity in human osteosarcoma cells. In all three breeds, osteosarcoma-associated loci and regions of reduced heterozygosity are enriched for genes in pathways connected to bone differentiation and growth. Several pathways, including one of genes regulated by miR124, are also enriched for somatic copy-number changes in tumors. Conclusions: Mapping a complex cancer in multiple dog breeds reveals a polygenic spectrum of germline risk factors pointing to specific pathways as drivers of disease

Quark-gluon vertex in general kinematics

The original publication can be found at www.springerlink.com Submitted to Cornell University’s online archive www.arXiv.org in 2007 by Jon-Ivar Skullerud. Post-print sourced from www.arxiv.org.We compute the quark–gluon vertex in quenched lattice QCD in the Landau gauge, using an off-shell mean-field O(a)-improved fermion action. The Dirac-vector part of the vertex is computed for arbitrary kinematics. We find a substantial infrared enhancement of the interaction strength regardless of the kinematics.Ayse Kizilersu, Derek B. Leinweber, Jon-Ivar Skullerud and Anthony G. William

Top 10 differentially expressed genes by the risk haplotype at each locus.

<p>Top 10 differentially expressed genes by the risk haplotype at each locus.</p

List of significantly associated haplotypes.

<p>List of significantly associated haplotypes.</p

Two neighboring loci on chromosome 5 are independently associated with disease risk.

<p>A. The top SNP of the first peak (29 Mb) is in high LD with nearby variants and shows no evidence of linkage to the top SNPs in the second peak (33 Mb). B. The 29 Mb peak is comprised of two haplotype blocks, and C. the risk haplotypes for the 29 Mb peak are rather common in the population. Similarly, D. the second peak also shows no linkage with the first peak in the combined analysis, whereas E. analysis of only B-cell lymphoma shows SNPs in strong LD within the second peak and in moderate LD with SNPs in the first peak. The top SNPs in the combined analysis and B-cell-lymphoma-only analysis are independent, and F. make up separate haplotypes at the second locus. G. Both risk haplotypes at the second locus are rare. Color-coding of SNPs in A, D, E, reflects their r² value relative the top SNP of that region, ranging from grey (not in LD) to red (strong LD).</p

Differentially expressed genes by the risk alleles at 29 Mb and 33 Mb play important role in T-cell immunity.

<p>A. The risk allele at the 29 Mb at homozygous state has a clear cis-regulation effect on the expression levels of <i>TRPC6</i>, <i>KIAA1377</i>, and <i>ANGPTL5</i>, three of the most proximal genes. <i>BIRC3</i>, which is also proximal to the 29 Mb risk locus, had a significant p-value, however the FDR value was slightly above the threshold of 0.05. The risk allele at 29 Mb was also associated with a regulatory effect on genes near the 33 Mb locus and a change in the expression of <i>PIK3R6</i> significantly. B. A large network of molecules that play a major role in activation of T-lymphocyte and other immune cells (IPA category: cell-to-cell signaling and interaction, hematological system development and function). This network includes 15 molecules of which expressions are significantly altered in individuals carrying at least one copy of the shared risk allele at the 33 Mb locus. The outcomes of such expression changes are significantly linked to decrease in T-cell activation.</p