DOI: 10.25675/10217/208318
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"

description: This dataset includes genotyping data for 267 US Golden Retrievers, obtained under CSU IACUC Protocol #13-4473A. Samples were recruited from the privately-owned pet population from October 2013 – May 2015 as part of a larger case-control study with the goal of understanding genetic and environmental risk factors for T zone Lymphoma. Blood samples were genotyped using the Illumina CanineHD BeadChip. Dogs were categorized as case, TZUS, or control. The list of individuals provided has undergone quality control filtering, including: 1) removing dogs with call rates &lt;97.5%, 2) removing dogs of European origin, and 3) removing highly related individuals (half-sibling or closer). For our analysis, we additionally did QC on the SNP dataset, including removing SNPs with call rates &lt;97.5 or minor allele frequency &lt;5%. However, the .bed and .bim files provided are unfiltered.
description: 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=1.18–1.19, p=.3x10-5–5.1x10-5) 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=1.24–1.42, p= 2.7x10-7–7.5x10-5) 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.