Regions of the Canine Genome Associated with Osteosarcoma Identified by a Whole Genome Case-Control Association Study Kenine E Comstock , Elinor Karlsson, Claire Wade, Evan T Keller, Eric Lander, Laurence Baker, Kerstin Lindblad-Toh
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with Osteosarcoma Identified by a Whole Genome
Case-Control Association Study
Kenine E Comstock, Elinor Karlsson, Claire Wade, Evan T Keller, Eric Lander,
Laurence Baker, Kerstin Lindblad-Toh
University of Michigan, Ann Arbor & Broad Institute, Boston, USA
The first example: Renal cancer syndrome
Canine Hereditary Multifocal Renal
Cystadenocarcinoma and Nodular Dermatofibrosis (RCND)
Lingaas and Comstock, et al. Hum Mol Genet. 2003 12(23):3043-53
1. Linkage mapping using families
Best for rare, high penetrance diseases
2. Association mapping
For complex traits
Compares cases vs controls
No need for families
100,000 SNPs or more for humans
Only ~30,000 SNPs in dogs!
Can narrow associated regions to kilobases
*Lindblad-Toh et al. Nature (2005) 438:803-19
Alaska gray wolf
India gray wolf
Spanish gray wolf
Italian Greyhound2.5 million SNPs discovered (1 SNP/kb)
Designed and tested by Michigan/Broad group
in collaboration with Affymetrix
~26,500 optimized SNP Mapping Set
Now commercially available
*In humans, would need approx 800 + 800
Yes! Power calculations appear correct
*Elinor Karlsson and Claire Wade, Broad Institute
1) Mastiff-type breeds
2) Long-limbed breeds
Greyhound-5 to 10 X
Rottweiler-5 X increased risk
Cases: Dogs diagnosed with osteosarcoma
Cases were confirmed by either radiography and/or by biopsy.
All cases are being confirmed by a single independent pathologist.
Controls: Healthy, cancer-free dogs
10 years and older for Greyhounds,
8 years and older for all other breeds.
Owners of control dogs are contacted regularly.
All dogs of a single breed in the study are unrelated
through the grandparents.
Table 1: Samples collected as of May 1, 2006
Haplotype The series of alleles along a chromosome inherited by an individual from one parent.
xStage 1: OSA susceptibility gene mapping in each breed separately
We’ve started with Rottweilers:
Searched genome for 0.5-1 Mb disease-associated haplotypes
Stage 2: Fine mapping across dog breeds within a breed group
Add related breeds to narrow the region to a smaller, shared ancestral haplotype (~10-20kb). We are just getting started with this!
Likelihood of an association
Location in the genome
SNPs grouped into 4 gamete “haplotype” blocksRegions associated with osteosarcoma in Rottweilers
-log(10) of the p-value
Henrik von Euler
Frode Lingaas (Oslo)
Guillermo Couto (Ohio)
Jaime Modiano (Denver)
Elaine Ostrander (NHGRI)
Bill Kisseberth (Ohio)
Cheryl London (Ohio)
Elizabeth McNiel (Minnesota)
Barbara Kitchell (Michigan State)
Karen Michalski (Serenity Animal Hosp)
Chieko Azuma (Tufts)
David Vail (Colorado)
Chand Khanna (NCI)
This study was funded in part by the Canine Health Foundation.
Dog photos were provided by Warren Photographic.