README file for TZL_Avery_cf3_phenoDetails.csv

Title: Dataset associated with "Genome-wide association analysis of canine T zone lymphoma identifies link to hypothyroidism and a shared association with mast-cell tumors"

Abstract:
Background: T zone lymphoma (TZL), a histologic variant of peripheral T cell lymphoma, represents about 12% of all canine lymphomas. Golden Retrievers appear predisposed, representing over 40% of TZL cases. Prior research found that asymptomatic aged Golden Retrievers frequently have populations of T zone-like cells (phenotypically identical to TZL) of undetermined significance (TZUS), potentially representing a pre-clinical state. These findings suggest a genetic risk factor for this disease and caused us to investigate potential genes of interest.

Methods: Privately-owned U.S. Golden Retrievers were categorized as TZL (n=95), TZUS (n=142), or control (n=101) using flow cytometry and genotyped using the Illumina CanineHD BeadChip. Single nucleotide polymorphism (SNP)-specific associations were evaluated using a mixed linear model adjusting for population stratification. Associated regions were subsequently sequenced using a custom sequence capture array (NimbleGen SeqCap EZ Developer Kit) on an Illumina NextSeq 500.

Results:  We found association with genome-wide significance in regions on chromosomes 8 and 14. The chromosome 14 peak included four SNPs (Odds Ratio=1.181.19, p=.3x10-55.1x10-5) near three hyaluronidase genes (SPAM1, HYAL4, and HYALP1). Targeted resequencing of this region identified missense mutations in all three genes; the variant in SPAM1 was predicted to be damaging. These mutations were also associated with risk for mast cell tumors among Golden Retrievers in an unrelated study. The chromosome 8 peak contained 7 SNPs (Odds Ratio=1.241.42, p= 2.7x10-77.5x10-5) near genes involved in thyroid hormone regulation (DIO2 and TSHR). A prior study from our laboratory found hypothyroidism is inversely associated with TZL risk. No coding mutations were found with targeted resequencing but identified variants may play a regulatory role for all or some of the genes. 

Conclusions: The pathogenesis of canine TZL may be related to hyaluronan breakdown and subsequent production of pro-inflammatory and pro-oncogenic byproducts.  The association on chromosome 8 may indicate thyroid hormone is involved in TZL development, consistent with findings from a previous study evaluating epidemiologic risk factors for TZL. Future work is needed to elucidate these mechanisms. 

Contact: Julia D. Labadie; jdlabadie@gmail.com

Data Citation: Labadie, J.D., Elvers, I., Spencer Feigelson, H., Magzamen, S., Yoshimoto, J., Dossey, J., Burnett, R., & Avery, A.C. (2020). Dataset associated with Genome-wide association analysis of canine T zone lymphoma identifies link to hypothyroidism and a shared association with mast-cell tumors. Colorado State University. Libraries. http://dx.doi.org/10.25675/10217/208318

Spatial Coverage: Samples represent dogs from throughout the US. 

Temporal Coverage: 2013-10-01  2015-05-31.

File Information: This file includes the phenotype information for each individual dog. The first 4 columns are in plink .fam format (https://www.cog-genomics.org/plink/1.9/formats#fam)

Variable Information:
#FID: No dogs were known to be related, so FID column is just IID repeated
#IID: Unique identifier for each dog
#Sex: 2=female, 1=Male
#Pheno: 2=case, 1=control (in this dataset, both TZUS and Controls were marked as 1)
#DiseaseType: Detailed disease status, categorized as TZL_case, TZUS, Control (described in manuscript)
#Organism: Genus species
#Breed: Dog breed; all samples were Golden Retrievers
#Tissue: Tissue DNA was extracted from 


