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

Elinor K Karlsson12*, Snaevar Sigurdsson13, Emma Ivansson13, Rachael Thomas4, Ingegerd Elvers13, Jason Wright1, Cedric Howald1, Noriko Tonomura15, Michele Perloski1, Ross Swofford1, Tara Biagi1, Sarah Fryc1, Nathan Anderson1, Celine Courtay-Cahen6, Lisa Youell6, Sally L Ricketts7, Sarah Mandlebaum8, Patricio Rivera9, Henrik von Euler10, William C Kisseberth11, Cheryl A London12, Eric S Lander1, Guillermo Couto1113, Kenine Comstock8, Mike P Starkey6, Jaime F Modiano1415, Matthew Breen164 and Kerstin Lindblad-Toh13*

Author Affiliations

1 Broad Institute of MIT and Harvard, Cambridge, MA, USA

2 FAS Center for Systems Biology, Harvard University, Cambridge, MA, USA

3 Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden

4 Department of Molecular Biomedical Sciences, College of Veterinary Medicine & Center for Comparative Medicine and Translational Research, North Carolina State University, Raleigh, NC, USA

5 Department of Clinical Sciences, Cummings School of Veterinary Medicine at Tufts University, North Grafton, MA, USA

6 Oncology Research Group, Animal Health Trust, Newmarket, Suffolk, UK

7 Canine Genetics Research Group, Animal Health Trust, Newmarket, Suffolk, UK

8 Department of Urology, University of Michigan, Ann Arbor, MI, USA

9 Department of Animal Breeding and Genetics, Uppsala University, Uppsala, Sweden

10 Department of Clinical Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden

11 Department of Veterinary Clinical Sciences and Veterinary Medical Center, The Ohio State University, Columbus, OH, USA

12 Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA

13 Couto Veterinary Consultants, Hilliard, OH, USA

14 Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

15 Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, MN, USA

16 Cancer Genetics Program, UNC Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

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Genome Biology 2013, 14:R132  doi:10.1186/gb-2013-14-12-r132

Published: 12 December 2013

Additional files

Additional file 1: Figure S1:

Regions of association defined with LD clumping. Figure S2. Ages of affected and unaffected samples. Figure S3. Phenotype variance explained at different association thresholds. Figure S4. The difference in genotype relative risk between cases and controls persists at more stringent significance thresholds. Figure S5. Cross-breed meta-analysis of OS GWAS datasets. Figure S6. Transcription factor motif analysis of top candidate variant. Figure S7. Size distribution of fixed and RRV regions by breed. Figure S8. CGH penetrance plots of dog and human OS. Figure S9. Dog GWAS results in human OS associated regions. Figure S10. Confidence interval comparison. Table S1. Association at top SNPs when sex is included as a covariate in the EMMAX genomewide analysis. Table S2. Top associated variants in the greyhound finemapping and imputation analysis. Table S3. Meta-analysis of nine breeds at the top candidate variant. Table S4. GRAIL keywords over-represented among genes in more than one osteosarcoma GWAS region. Table S5. Association between top GWAS SNPs and CGH gain/loss in matched germline tumor samples, controlling for breed clusters using Cochran-Mantel-Haenszel (CMH) test. Table S6. Osteosarcoma related microRNA sets curated from literature for INRICH testing.

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