Variants within the SP110 nuclear body protein modify risk of canine degenerative myelopathy

Emma L. Ivansson; Kate Megquier; Sergey V. Kozyrev; Eva Murén; Izabella Baranowska Körberg; Ross Swofford; Michele Koltookian; Noriko Tonomura; Rong Zeng; Ana L. Kolicheski; Liz Hansen; Martin L. Katz; Gayle C. Johnson; Gary S. Johnson; Joan R. Coates; Kerstin Lindblad-Toh

doi:10.1073/pnas.1600084113

New Research In

Edited by Stephen T. Warren, Emory University School of Medicine, Atlanta, GA, and approved April 15, 2016 (received for review January 7, 2016)

Significance

Degenerative myelopathy (DM) is a canine disease very similar to amyotrophic lateral sclerosis (ALS) in humans. We previously showed that DM is a promising model for ALS, because genome-wide association identified a mutation in superoxide dismutase 1 gene (SOD1), a known ALS gene. This mutation found in many dog breeds increases the risk of DM, and the pathological findings and clinical progression of the two diseases are similar. In this study, we identify a modifier gene, SP110 nuclear body protein (SP110), which strongly affects overall disease risk and age of onset in Pembroke Welsh Corgis at risk for DM. Dissecting the complex genetics of this disease in a model organism may lead to new insights about risk and progression in both canine and human patients.

Abstract

Canine degenerative myelopathy (DM) is a naturally occurring neurodegenerative disease with similarities to some forms of amyotrophic lateral sclerosis (ALS). Most dogs that develop DM are homozygous for a common superoxide dismutase 1 gene (SOD1) mutation. However, not all dogs homozygous for this mutation develop disease. We performed a genome-wide association analysis in the Pembroke Welsh Corgi (PWC) breed comparing DM-affected and -unaffected dogs homozygous for the SOD1 mutation. The analysis revealed a modifier locus on canine chromosome 25. A haplotype within the SP110 nuclear body protein (SP110) was present in 40% of affected compared with 4% of unaffected dogs (P = 1.5 × 10⁻⁵), and was associated with increased probability of developing DM (P = 4.8 × 10⁻⁶) and earlier onset of disease (P = 1.7 × 10⁻⁵). SP110 is a nuclear body protein involved in the regulation of gene transcription. Our findings suggest that variations in SP110-mediated gene transcription may underlie, at least in part, the variability in risk for developing DM among PWCs that are homozygous for the disease-related SOD1 mutation. Further studies are warranted to clarify the effect of this modifier across dog breeds.

Footnotes

↵¹To whom correspondence may be addressed. Email: emma.ivansson{at}ki.se or kersli{at}broadinstitute.org.
↵²Present address: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77, Stockholm, Sweden.
↵³Present address: Department of Women’s and Children’s Health, Karolinska Institutet, Karolinska University Hospital Solna, 171 76, Stockholm, Sweden.

Author contributions: E.L.I. and K.L.-T. designed research; E.L.I., K.M., S.V.K., E.M., I.B.K., R.S., M.K., N.T., R.Z., A.L.K., L.H., M.L.K., G.C.J., G.S.J., J.R.C., and K.L.-T. performed research; E.L.I., K.M., and S.V.K. analyzed data; and E.L.I. and K.M. wrote the paper.
Conflict of interest statement: A DNA test to identify dogs at risk of developing degenerative myelopathy is the subject of four awarded patents (European Patent 2247752, Australian Patent 2009212473, Japanese Patent 5584916, and Mexico Patent 326951) and one pending patent application (Canada Patent 2,714,393). Three of the coauthors (G.S.J., J.R.C., and K.L.-T.) are co-inventors listed on these patents and patent applications. A patent application was filed as to certain subject matter of this manuscript.
This article is a PNAS Direct Submission.
Data deposition: The National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) www.ncbi.nlm.nih.gov/geo accession numbers for the genome-wide association data presented in this paper are GSE80735 (PWC) and GSE80315 (Boxer). The NCBI Single Nucleotide Polymorphism Database (dbSNP) accession numbers for the Illumina MiSeq-detected variants reported in this paper are 1987230493–1987230525. The NCBI Sequence Read Archive (SRA) accession numbers for the whole-genome sequences of three PWCs reported in this paper are SRX745862–SRX745864. The GenBank accession numbers for the canine SP110 alternative transcripts reported in this paper are KP245899–KP245902.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1600084113/-/DCSupplemental.